Imidazole-based antimicrobial agents

ABSTRACT

The present invention relates to therapeutic agents suitable for use in the treatment of microbial infection in mammals. The present invention further relates to the use of pharmaceutical compositions comprising said agents in the treatment of medical conditions in mammals, in particular in the treatment of microbial infection. The agents and pharmaceutical compositions of the invention are of particular relevance in the treatment of diseases associated with antibiotic-resistant microbes. In one particular embodiment, the pharmaceutical composition can have the structural moiety of formula (I) or a pharmaceutically-acceptable salt of said compound: 
                         
wherein group A is selected from the formulae
 
                         
Group B is aryl, R 1  is an optionally substituted aryl ring, an optionally substituted benzyl ring, CH 3 , or C 2 to 6  alkyl, and R 2  is hydrogen, an alkyl group, a halogen, or —(CH 2 ) n N(CH 3 ) 2  where n is an integer from 1 to 3.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national stage entry of International PatentApplication No. PCT/EP2015/078587 having a filing date of Dec. 3, 2015,which claims priority to and the benefit of European Patent ApplicationNo, 14196335.5 filed in the European Patent Office on Dec. 4, 2014, theentire contents of which are incorporated herein by reference.

The present application claims priority from European Patent ApplicationEP 14196335, the content of which is hereby incorporated by reference inits entirety.

FIELD OF INVENTION

The present invention relates to novel therapeutic agents suitable foruse in the treatment of mammalian disease and in particular to noveltherapeutic agents suitable for use in the treatment of microbialinfection in mammals. The present invention further relates to the useof pharmaceutical compositions comprising said agents in the treatmentof medical conditions in mammals, in particular in the treatment ofmicrobial infection. The agents and pharmaceutical compositions of theinvention are of particular relevance in the treatment of diseasesassociated with antibiotic-resistant microbes.

BACKGROUND OF THE INVENTION

Antibiotic resistance is a serious and growing phenomenon incontemporary medicine and has emerged as one of the pre-eminent publichealth concerns of the 21st century, especially in the case ofhospital-acquired infections. According to data from the Centers forDisease Control and Prevention (CDC) available in 2008, the sixso-called ESKAPE bacteria (Enterococcus faecium (gram positive),Staphylococcus aureus (gram positive), Klebsiella pneumoniae (gramnegative), Acinetobacter baumanii (gram negative), Pseudomonasaeruginosa (gram negative), and Enterobacter (gram negative)) areresponsible for two thirds of all health care-associated infections. Theincreasing prevalence of antibiotic-resistant bacterial infections seenin clinical practice stems from antibiotic use both within humanmedicine and veterinary medicine in which the use of antibiotics canincrease selective pressure in a population of bacteria to allow theresistant bacteria to thrive and the susceptible bacteria to die off.

Infection by several drug-resistant Gram-negative bacteria—such asmultidrug-resistant (MDR) Pseudomonas aeruginosa andcarbapenem-resistant Klebsiella species is of great concern. Thetherapeutic options for these pathogens are so limited that cliniciansare often forced to use older, previously discarded drugs, which areassociated with significant toxicity.

With respect to gram-positive bacteria, the percentage of bloodstreaminfections caused by antibiotic-resistant gram-positive bacteria isincreasing. As of 2006, approximately 60% of staphylococcal infectionsin intensive care units in the United States were caused bymethicillin-resistant Staphylococcus aureus (MRSA), with percentagescontinuing to rise. Hospital-acquired MRSA strains are generallymultidrug-resistant. As a means of highlighting the scale of the problemat hand, more people now die of MRSA infection in US hospitals than ofHIV/AIDS and tuberculosis combined. Vancomycin is the standard treatmentfor serious MRSA infections, but cases of vancomycin-resistantStaphylococcus aureus (VRSA) also emerge. The increase in resistantGram-positive strains may be explained, in part, by scientistsconcentrating in the 1970s and 1980s on the development of drugs activeagainst Gram-negative pathogens, thereby permitting the slow evolutionand selection of resistant Gram-positive bacteria.

Furthermore, multi-drug resistant (MDR) infections are also increasingand infections now occur that are resistant to all current antibacterialoptions (so-called pan-antibiotic-resistance). As resistance towardsantibiotics becomes more common, a greater need for alternativetreatments arises. However, despite a push for new antibiotic therapies,there has been a continued decline in the number of newly approveddrugs. Antibiotic resistance and, in particular, the antibioticresistance of gram-positive bacteria therefore poses a significantglobal health problem.

U.S. Pat. No. 4,012,414 discloses 2-furylimidazoles in which, with theexception of the bond to the furan ring, the imidazoles areunsubstituted. These compounds are disclosed to be suitable for use asantidepressants.

EP 0251380 discloses 2-furanylimidizoles for use as cardiotonic agentswhereby the two carbon atoms of the imidazole ring which are not bondedto the furan ring may be substituted with H, methyl or ethyl.

It is therefore an object of the present invention to provide chemicalspecies which can overcome the above-highlighted deficiencies in thetreatment of mammalian microbial infections, in particular thoseresulting from gram-positive bacteria, and especially gram-positivebacteria strains known to show resistance to existingantibiotics/therapies.

SUMMARY OF THE INVENTION

The present invention relates to novel therapeutic agents suitable foruse in the treatment of mammalian disease and in particular to noveltherapeutic agents suitable for use in the treatment of microbialinfection.

In particular, the present invention relates to a compound comprising orconsisting of the structural moiety of formula (I) or apharmaceutically-acceptable salt of said compound, for use as amedicament

wherein(i) Y is C or N;(ii) R¹ and R² are independently selected from the group consisting of:H, —CH₃, C_(2to6)alkyl, C_(3to6)cycloalkyl, halogen, —(CH₂)_(n)N(CH₃)₂where n is an integer from 1 to 3, benzyl optionally substituted on thephenyl ring, heteroaryl, and aryl,with the proviso that at least one of R¹ or R² possesses 3 or morecarbon atoms; orR¹ and R² are connected to form a four-, five- or six-memberednon-aromatic carbocyclic ring thus providing a fused bicyclic moiety inwhich one or more of the carbon atoms of the ring comprising groups R¹and R² is optionally replaced by a heteroatom selected from O, N, or S,and where one or more of the atoms of the ring comprising groups R¹ andR² is optionally substituted with one or more substituents independentlyselected from the group consisting of —CH₃, C_(2to4)alkyl, halogen,hydroxyl, —OCH₃, —OC_(2to4)alkyl, ethynyl, —OCF₃, and —CF₃;

-   -   with the proviso for all of the above-mentioned alternatives        that when:        Y is N, R² represents a lone pair of electrons belonging to the        N atom; and        (iii) A is aryl or heteroaryl; and        (iv) B is aryl, heteroaryl, a bicyclic system comprising at        least one aromatic ring, or styryl.

Preferred embodiments of the invention are evident from the dependentclaims.

The invention also relates to the use of compounds comprising the moietyof formula (I) or a pharmaceutically-acceptable salt of said compound,for use in the treatment of mammalian microbial infection.

In the present invention, in the structural moiety of formula (I) A ispreferably 5-membered heteroaryl, and when A is 5-membered heteroaryl, Ais preferably selected from the group consisting of

where * is the point of connection to the correspondingly-labeled atomof B and ** is the point of connection to the correspondingly-labeledatom of,

wherein the aromatic ring of A is optionally substituted, preferably byone or more substituents independently selected from —CH₃,C_(2to4)alkyl, halogen, —OCH₃, and —OC_(2to4)alkyl. When aromatic ringof A is substituted by one or more substituents, aromatic ring of A ismore preferably substituted by one or more substituents independentlyselected from —CH₃, C_(2to4)alkyl, and halogen, most preferably by oneor more —CH₃ substituents.

In the present invention, in the structural moiety of formula (I) B ispreferably selected from the group consisting of

where * is the point of connection to the correspondingly-labeled atomof A. When B is a phenyl ring, the phenyl ring may optionally besubstituted. When B is a substituted phenyl ring, the phenyl ring ispreferably substituted with one or more substituents independentlyselected from the group consisting of —CH₃, C_(2to4)alkyl, halogen,hydroxyl, —OCH₃, —OC_(2to4)alkyl, —CF₃, —OCF₃, —NH₂, —CH₂NH₂, —N(CH₃)₂,—NO₂, —CH₂OH, —CO₂CH₃, —CO₂C_(2to4)alkyl, —CO₂H, —N(alkyl)₂ where thetwo alkyl groups are independently selected from —CH₃ or C_(2to4)alkyl,—NH(alkyl) where the alkyl group is selected from —CH₃ or C_(2to4)alkyl,4-morpholinyl, 1-piperidinyl, 4H-piperazinyl,4-C_(1to4)alkyl-piperazinyl, and 4-C_(3to6)cycloalkyl-piperazinyl,preferably independently selected from the group consisting of —CH₃,C_(2to4)alkyl, iso-propyl, tert-butyl, halogen wherein halogen ispreferably F or Cl or Br, hydroxyl, —OCH₃, —CF₃, —OCF₃, —N(CH₃)₂, —NO₂,and 4-methylpiperazinyl, more preferably independently selected from thegroup consisting of —CH₃, —CH₂CH₃, iso-propyl, —N(CH₃)₂, halogen whereinhalogen is preferably F or Cl or Br, —OCH₃, —CF₃, and —OCF₃.

In the structural moiety of formula (I), when B is other than aunsubstituted or substituted phenyl ring, B may be optionallysubstituted, and when B is substituted it is preferably substituted withone or more substituents independently selected from the groupconsisting of —CH₃, C_(2to4)alkyl, halogen wherein halogen is preferablyF or Cl or Br, hydroxyl, —OCH₃, —OC_(2to4)alkyl, —CF₃, —OCF₃, —CO₂CH₃,—CO₂C_(2to4)alkyl, and —CO₂H, more preferably selected from the groupconsisting of —CH₃, —CF₃, —OCF₃ and halogen, wherein halogen ispreferably F or Cl or Br.

The term “styryl” as used in the present application is to be understoodto mean the following structural moiety

where * is the point of connection to the correspondingly-labeled atomof A, and preferably to mean

In the present invention, when R¹ and R² are connected to form a four-,five- or six-membered non-aromatic carbocyclic ring thus providing afused bicyclic moiety in the structural moiety of formula (I), thebicyclic moiety is preferably selected from the group consisting of

-   -   where m is 0, 1 or 2, and is most preferably 2, and ** is the        point of connection to the correspondingly-labeled atom of A.

In the structural moiety of formula (I) of the present invention, whenR¹ or R² is benzyl optionally substituted on the phenyl ring, they arepreferably substituted with one or more substituents independentlyselected from the group consisting of —CH₃, C_(2to4)alkyl, halogen,hydroxyl, —OCH₃, —OC_(2to4)alkyl, ethynyl, —OCF₃, and —CF₃, morepreferably with one or more substituents independently selected from thegroup consisting of halogen and hydroxyl, and are most preferably4-halobenzyl, for example 4-bromobenzyl.

In the structural moiety of formula (I) of present invention, when R¹ orR² is aryl they are preferably substituted or unsubstituted phenyl, andwhen they are substituted phenyl they are preferably phenyl substitutedwith one or more substituents independently selected from the groupconsisting of —CH₃, C_(2to4)alkyl, halogen, hydroxyl, —OCH₃,—OC_(2to4)alkyl, ethynyl, —OCF₃, and —CF₃, more preferably with one ormore substituents independently selected from the group consisting of—CH₃, —CH₂CH₃, —OH, —CF₃, —OCF₃, ethynyl, and halogen, wherein halogenis preferably F or Cl or Br, most preferably with one or moresubstituents independently selected from the group consisting of —CH₃,—CH₂CH₃, —CF₃, —OCF₃, ethynyl, and halogen, wherein halogen ispreferably F or Cl or Br.

In the structural moiety of formula (I) of the present invention, whenR¹ is aryl, heteroaryl, or benzyl or benzyl substituted on the phenylring, and Y is C, R² is preferably —CH₃, —CH₂N(CH₃)₂, Cl, or H. In someembodiments R² is —CH₃. In some embodiments R² is —CH₂N(CH₃)₂. In someembodiments R² is Cl. In some embodiments R² is H.

In the structural moiety of formula (I) of the present invention, whenR² is aryl, heteroaryl, or benzyl or benzyl substituted on the phenylring, R¹ is preferably —CH₃, —CH₂N(CH₃)₂, Cl, or H. In some embodimentsR¹ is —CH₃. In some embodiments R¹ is —CH₂N(CH₃)₂. In some embodimentsR¹ is Cl. In some embodiments R¹ is H.

In some embodiments of the present invention, in the structural moietyof formula (I) R¹ and R² are preferably independently selected from thegroup consisting of H, —CH₃, n-propyl, n-butyl, iso-butyl,4-bromobenzyl, 4-hydroxybenzyl, —CH₂N(CH₃)₂, halogen where halogen ispreferably Cl, and phenyl, where phenyl is optionally substituted withone or more substituents independently selected from —CH₃, —CH₂CH₃, —OH,—CF₃, —OCF₃, ethynyl, and halogen, wherein halogen is preferably F or Clor Br, and are more preferably independently selected from the groupconsisting of H, —CH₃, 4-bromobenzyl, —CH₂N(CH₃)₂, halogen where halogenis preferably Cl, and phenyl, where phenyl is optionally substitutedwith one or more substituents independently selected from —CH₃, —CH₂CH₃,—CF₃, —OCF₃, ethynyl, and halogen, wherein halogen is preferably F or Clor Br.

In some preferred embodiments of the invention, when R¹ is H, R² is notH and when R² is H, R¹ is not H.

In some preferred embodiments of the invention, when R¹ is —CH₃, R² isnot H and when R² is —CH₃, R¹ is not H.

In some preferred embodiments of the invention when R¹ is aryl,heteroaryl, or benzyl or benzyl or benzyl substituted on the phenylring, then when Y is C, R² is H, —CH₃, —CH₂N(CH₃)₂, or halogen wherehalogen is preferably Cl.

In some preferred embodiments of the invention when R² is aryl,heteroaryl, or benzyl or benzyl substituted on the phenyl ring, R¹ is H,—CH₃, —CH₂N(CH₃)₂, or halogen where halogen is preferably Cl.

In the remainder of the application, unless specified otherwise allgeneric groups R¹, R², A, B, Y, m are as defined for the moiety offormula (I) and regardless of whether these groups have been furtherdefined and/or restricted relative to their most generic nature in thestructural moiety of formula (I), the provisos stipulated for thestructural moiety of formula (I) apply for all structures, formulae andembodiments herein.

Hereinafter, when reference is made to a group/substituent being “asdefined for formula (I)”, “as defined for the moieties of formula (I)”etc, e.g. “In the moiety of List 1, R¹, R², group A and group B are asdefined for formula (I)”, this is to be understood to mean all possibledefinitions of the respective groups/substituents as describedhereinabove for formula (I), including any of the “preferred”, “morepreferred” variants of a particular group/substituent. Moreover, anyspecific examples or lists of groups or substituents which are statedhereinabove to be “preferred”, “more preferred” etc for the moieties offormula (I) are also to be understood to be “preferred”, “morepreferred” etc for any of the formulae listed hereinafter which fallunder the wider scope of formula (I).

Hereinafter, when a formula or specific compound is depicted in such away that the full valency of an atom, for example a heteroatom, wouldappear not to be satisfied, it is to be understood that the valency ofsaid atom is satisfied through the presence of non-depicted hydrogenatoms, i.e. the depicted species is not a radical, cation, anion,carbine etc., but instead a neutral species. By way of example, thefollowing structures/situations are presented:

Structural moieties depicted as

are to be understood to respectively represent

Moreover, in certain cases herein graphical depictions for a givenspecific structural moiety which are equally understood by the skilledperson but which are different from one another are used. These are tobe understood to represent the structural moiety that the skilled personwould understand upon analyzing said moiety in isolation and not throughcomparison to other depictions of the same moiety presented elsewhereherein. For example, a methyl group may be depicted by explicitlywriting the formula “CH₃” or may be equally depicted using the standard“linear” formula which is equally well understood by the skilled person.The following two structures thus both comprise a methyl group:

DETAILED DESCRIPTION OF THE INVENTION

When a compound of the invention can exist in different tautomericforms, the present invention includes any possible tautomers andpharmaceutically acceptable salts thereof, and mixtures thereof, exceptwhere specifically drawn or stated otherwise. For example, imidazoleswhich have no N-substitution are known to exist in two tautomeric formsin which the —NH hydrogen atom may reside on either of the nitrogenatoms of the imidazole ring. In such an instance where only onetautomeric form is graphically depicted in the present invention, itscorresponding tautomer may be implicitly included. For example, when thefollowing structure is depicted,

its corresponding tautomer

may be implicitly also included. This applies for all structures andmoieties of the invention which may exist in different tautomeric forms.

In a preferred embodiment of the invention, the moiety of formula (I) isrepresented by the formula (III) shown in List 1.

In the moiety of List 1, R¹, R², group A and group B are as defined forformula (I).

In some embodiments of the invention, the moiety of formula (I) isselected from the formulae comprised in List 1a.

In the formulae of List 1a, R¹, R² and B are as defined for moieties offormula (I) and the rings which correspond to group A of formula (I)(i.e. the furan, thiophene, pyrrole, etc rings) may be optionallysubstituted, preferably by one or more substituents independentlyselected from —CH₃, C_(2to4)alkyl, halogen, —OCH₃, and —OC_(2to4)alkyl,more preferably by one or more substituents independently selected from—CH₃, C_(2to4)alkyl, and halogen, most preferably by one or more —CH₃substituents.

In the moieties of Lists 1 and 1a, one of R¹ and R² is preferably benzyloptionally substituted on the phenyl ring, or heteroaryl, or aryl, eachof said benzyl optionally substituted on the phenyl ring, or heteroaryl,or aryl being as defined for formula (I) above.

In some embodiments of the invention, the moiety of formula (I) isselected from the formulae comprised in List 2.

In the formulae of List 2, B is as defined for moieties of formula (I)and R² is selected from the group consisting of H, —CH₃, C_(2to6)alkyl,C_(3to6)cycloalkyl, halogen, and —(CH₂)_(n)N(CH₃)₂ where n is an integerfrom 1 to 3, preferably selected from the group consisting of H, —CH₃,n-propyl, n-butyl, iso-butyl, —CH₂N(CH₃)₂, and halogen where halogen ispreferably Cl, and more preferably selected from the group consisting ofH, —CH₃, —CH₂N(CH₃)₂, and halogen where halogen is preferably Cl, R³represents optional substituents on an otherwise unsubstituted phenylring and is preferably one or more substituents independently selectedfrom the group consisting of —CH₃, C_(2to4)alkyl, halogen, hydroxyl,—OCH₃, —OC_(2to4)alkyl, ethynyl, —OCF₃, and —CF₃, more preferably one ormore substituents independently selected from the group consisting of—CH₃, —CH₂CH₃, —OH, —CF₃, —OCF₃, ethynyl, and halogen, wherein halogenis preferably F or Cl or Br, most preferably independently selected fromone or more substituents selected the group consisting of —CH₃, —CH₂CH₃,—CF₃, —OCF₃, ethynyl, and halogen, wherein halogen is preferably F or Clor Br, and the rings which correspond to group A of formula (I) (e.g.the furan, thiophene, pyrrole rings) may be optionally substituted,preferably by one or more substituents independently selected from —CH₃,C_(2to4)alkyl, halogen, —OCH₃, and —OC_(2to4)alkyl, more preferably byone or more substituents independently selected from —CH₃,C_(2to4)alkyl, and halogen, most preferably by one or more —CH₃substituents.

In some embodiments of the invention, the moiety of formula (I) isselected from the formulae comprised in List 3.

In the formulae of List 3, R¹ and R² are as defined for formula (I) andR⁴ to R⁸ are independently selected from the group consisting of H,—CH₃, C_(2to4)alkyl, halogen, hydroxyl, —OCH₃, —OC_(2to4)alkyl, —CF₃,—OCF₃, —NH₂, —CH₂NH₂, —N(CH₃)₂, —NO₂, —CH₂OH, —CO₂CH₃,—CO₂C_(2to4)alkyl, —CO₂H, —N(alkyl)₂ where the two alkyl groups areindependently selected from —CH₃ or C_(2to4)alkyl, —NH(alkyl) where thealkyl group is selected from —CH₃ or C_(2to4)alkyl, 4-morpholinyl,1-piperidinyl, 4H-piperazinyl, 4-C_(1to4)alkyl-piperazinyl, and4-C_(3to6)cycloalkyl-piperazinyl, preferably independently selected fromthe group consisting of H, —CH₃, C_(2to4)alkyl, iso-propyl, tert-butyl,halogen wherein halogen is preferably F or Cl or Br, hydroxyl, —OCH₃,—CF₃, —OCF₃, —N(CH₃)₂, —NO₂, and 4-methylpiperazinyl, more preferablyindependently selected from the group consisting of H, —CH₃, —CH₂CH₃,iso-propyl, —N(CH₃)₂, halogen wherein halogen is preferably F or Cl orBr, —OCH₃, —CF₃, and —OCF₃, and the rings which correspond to group A offormula (I) (e.g. the furan, thiophene, pyrrole etc rings) may beoptionally substituted, preferably by one or more substituentsindependently selected from —CH₃, C_(2to4)alkyl, halogen, —OCH₃, and—OC_(2to4)alkyl, more preferably by one or more substituentsindependently selected from —CH₃, C_(2to4)alkyl or halogen, mostpreferably by one or more —CH₃ substituents. In a preferred embodimentof the invention, in the formulae of List 3 at least two, preferablythree or four, of R⁴, R⁵, R⁶, R⁷ and R⁸ are H.

In some embodiments of the invention, the moiety of formula (I) isselected from the formulae comprised in List 4.

In the formulae of List 4, R¹, R² and A are as defined for formula (I),R⁴ to R⁸ are independently selected from the group consisting of H,—CH₃, C_(2to4)alkyl, halogen, hydroxyl, —OCH₃, —OC_(2to4)alkyl, —CF₃,—OCF₃, —NH₂, —CH₂NH₂, —N(CH₃)₂, —NO₂, —CH₂OH, —CO₂CH₃,—CO₂C_(2to4)alkyl, —CO₂H, —N(alkyl)₂ where the two alkyl groups areindependently selected from —CH₃ or C_(2to4)alkyl, —NH(alkyl) where thealkyl group is selected from —CH₃ or C_(2to4)alkyl, 4-morpholinyl,1-piperidinyl, 4H-piperazinyl, 4-C_(1to4)alkyl-piperazinyl, and4-C_(3to6)cycloalkyl-piperazinyl, preferably independently selected fromthe group consisting of H, —CH₃, C_(2to4)alkyl, iso-propyl, tert-butyl,halogen wherein halogen is preferably F or Cl or Br, hydroxyl, —OCH₃,—CF₃, —OCF₃, —N(CH₃)₂, —NO₂, and 4-methylpiperazinyl, more preferablyindependently selected from the group consisting of H, —CH₃, —CH₂CH₃,iso-propyl, —N(CH₃)₂, halogen wherein halogen is preferably F or Cl orBr, —OCH₃, —CF₃ and —OCF₃, and all moieties corresponding to group B offormula (I) which are not unsubstituted- or substituted-phenyl may beoptionally substituted, and when substituted then preferably with one ormore substituents, preferably with one or two substituents,independently selected from the group consisting of —CH₃, C_(2to4)alkyl,halogen, hydroxyl, —OCH₃, —OC_(2to4)alkyl, —CF₃, —OCF₃, —CO₂CH₃,—CO₂C_(2to4)alkyl, and —CO₂H, more preferably independently selectedfrom the group consisting of halogen, —CH₃, —CF₃, and —OCF₃. In apreferred embodiment of the invention in which B corresponds to a phenylring in the formulae of List 4, at least two, preferably three or four,of R⁴, R⁵, R⁶, R⁷ and R⁸ are H.

In some embodiments of the invention, the moiety of formula (I) isselected from the formulae comprised in List 5.

In the formulae of List 5, R¹ and R² are as defined for formula (I), R⁴to R⁸ are independently selected from the group consisting of H, —CH₃,C_(2to4)alkyl, halogen, hydroxyl, —OCH₃, —OC_(2to4)alkyl, —CF₃, —OCF₃,—NH₂, —CH₂NH₂, —N(CH₃)₂, —NO₂, —CH₂OH, —CO₂CH₃, —CO₂C_(2to4)alkyl,—CO₂H, —N(alkyl)₂ where the two alkyl groups are independently selectedfrom —CH₃ or C_(2to4)alkyl, —NH(alkyl) where the alkyl group is selectedfrom —CH₃ or C_(2to4)alkyl, 4-morpholinyl, 1-piperidinyl,4H-piperazinyl, 4-C_(1to4)alkyl-piperazinyl, and4-C_(3to6)cycloalkyl-piperazinyl, preferably independently selected fromthe group consisting of H, —CH₃, C_(2to4)alkyl, iso-propyl, tert-butyl,halogen wherein halogen is preferably F or Cl or Br, hydroxyl, —OCH₃,—CF₃, —OCF₃, —N(CH₃)₂, —NO₂, and 4-methylpiperazinyl, more preferablyindependently selected from the group consisting of H, —CH₃, —CH₂CH₃,iso-propyl, —N(CH₃)₂, halogen wherein halogen is preferably F or Cl orBr, —OCH₃, —CF₃, and —OCF₃, and all moieties corresponding to group B offormula (I) which are not unsubstituted- or substituted-phenyl may beoptionally substituted, and when substituted then preferably with one ormore substituents, preferably with one or two substituents,independently selected from the group consisting of —CH₃, C_(2to4)alkyl,halogen, hydroxyl, —OCH₃, —OC_(2to4)alkyl, —CF₃, —OCF₃, —CO₂CH₃,—CO₂C_(2to4)alkyl, and —CO₂H, more preferably independently selectedfrom the group consisting of halogen, —CH₃, —CF₃, and —OCF₃, and allmoieties corresponding to group A of formula (I) (e.g. the furan,thiophene, pyrrole rings) may be optionally substituted, preferably byone or more substituents independently selected from —CH₃,C_(2to4)alkyl, halogen, —OCH₃, and —OC_(2to4)alkyl, more preferably byone or more substituents independently selected from —CH₃,C_(2to4)alkyl, and halogen, most preferably by one or more —CH₃substituents. In a preferred embodiment of the invention in which Bcorresponds to a phenyl ring in the formulae of List 5, at least two,preferably three or four, of R⁴, R⁵, R⁶, R⁷ and R⁸ are H.

In some embodiments of the invention, the moiety of formula (I) isselected from the formulae comprised in List 6.

In the formulae of List 6, A is as defined for moieties of formula (I),R² is selected from the group consisting of H, —CH₃, C_(2to6)alkyl,C_(3to6)cycloalkyl, halogen, —(CH₂)_(n)N(CH₃)₂ where n is an integerfrom 1 to 3, preferably selected from the group consisting of H, —CH₃,n-propyl, n-butyl, iso-butyl, —CH₂N(CH₃)₂, and halogen where halogen ispreferably Cl, more preferably selected from the group consisting of H,—CH₃, —CH₂N(CH₃)₂, and halogen where halogen is preferably Cl, R⁴ to R⁸are independently selected from the group consisting of H, —CH₃,C_(2to4)alkyl, halogen, hydroxyl, —OCH₃, —OC_(2to4)alkyl, —CF₃, —OCF₃,—NH₂, —CH₂NH₂, —N(CH₃)₂, —NO₂, —CH₂OH, —CO₂CH₃, —CO₂C_(2to4)alkyl,—CO₂H, —N(alkyl)₂ where the two alkyl groups are independently selectedfrom —CH₃ or C_(2to4)alkyl, —NH(alkyl) where the alkyl group is selectedfrom —CH₃ or C_(2to4)alkyl, 4-morpholinyl, 1-piperidinyl,4H-piperazinyl, 4-C_(1to4)alkyl-piperazinyl, and4-C_(3to6)cycloalkyl-piperazinyl, preferably independently selected fromthe group consisting of H, —CH₃, C_(2to4)alkyl, iso-propyl, tert-butyl,halogen wherein halogen is preferably F or Cl or Br, hydroxyl, —OCH₃,—CF₃, —OCF₃, —N(CH₃)₂, —NO₂, and 4-methylpiperazinyl, more preferablyindependently selected from the group consisting of H, —CH₃, —CH₂CH₃,iso-propyl, —N(CH₃)₂, halogen wherein halogen is preferably F or Cl orBr, —OCH₃, —CF₃, and —OCF₃, and all moieties corresponding to group B offormula (I) which are not unsubstituted- or substituted-phenyl may beoptionally substituted, and when substituted then preferably with one ormore, preferably with one or two, substituents independently selectedfrom the group consisting of —CH₃, C_(2to4)alkyl, halogen, hydroxyl,—OCH₃, —OC_(2to4)alkyl, —CF₃, —OCF₃, —CO₂CH₃, —CO₂C_(2to4)alkyl, and—CO₂H, more preferably independently selected from the group consistingof halogen, —CH₃, —CF₃, and —OCF₃, and R³ represents optionalsubstituents on an otherwise unsubstituted phenyl ring and is preferablyone or more substituents independently selected from the groupconsisting of —CH₃, C_(2to4)alkyl, halogen, hydroxyl, —OCH₃,—OC_(2to4)alkyl, ethynyl, —OCF₃, and —CF₃, more preferably one or moresubstituents independently selected from the group consisting of —CH₃,—CH₂CH₃, —OH, —CF₃, —OCF₃, ethynyl, and halogen, wherein halogen ispreferably F or Cl or Br, most preferably independently selected fromone or more substituents selected the group consisting of —CH₃, —CH₂CH₃,—CF₃, —OCF₃, ethynyl, and halogen, wherein halogen is preferably F or Clor Br. In a preferred embodiment of the invention in which B correspondsto a phenyl ring in the formulae of List 6, at least two, preferablythree or four, of R⁴, R⁵, R⁶, R⁷ and R⁸ are H.

In some embodiments, the moiety of formula (I) is represented by theformula (IV)

wherein A and B are as defined for formula (I), R² is selected from thegroup consisting of H, —CH₃, C_(2to6)alkyl, C_(3to6)cycloalkyl, halogen,and —(CH₂)_(n)N(CH₃)₂ where n is an integer from 1 to 3, preferablyselected from the group consisting of H, —CH₃, n-propyl, n-butyl,iso-butyl, —CH₂N(CH₃)₂, and halogen where halogen is preferably Cl, morepreferably selected from the group consisting of H, —CH₃, —CH₂N(CH₃)₂,and halogen where halogen is preferably Cl, and R³ represents optionalsubstituents on an otherwise unsubstituted phenyl ring and is preferablyone or more substituents independently selected from the groupconsisting of —CH₃, C_(2to4)alkyl, halogen, hydroxyl, —OCH₃,—OC_(2to4)alkyl, ethynyl, —OCF₃, and —CF₃, more preferably one or moresubstituents independently selected from the group consisting of —CH₃,—CH₂CH₃, —OH, —CF₃, —OCF₃, ethynyl, and halogen, wherein halogen ispreferably F or Cl or Br, most preferably independently selected fromone or more substituents selected the group consisting of —CH₃, —CH₂CH₃,—CF₃, —OCF₃, ethynyl, and halogen, wherein halogen is preferably F or Clor Br.

In some embodiments, in the moiety represented by the formula (IV) R² is—CH₃. In some embodiments, in the moiety represented by the formula (IV)R² is H. In some embodiments, in the moiety represented by the formula(IV) R² is —CH₂N(CH₃)₂. In some embodiments, in the moiety representedby the formula (IV) R² is Cl.

In some embodiments of the invention, the compounds comprising themoiety of formula (I) are represented by the formula (V)

wherein R¹, R² and A are as defined for formula (I), and R⁴ to R⁸ areindependently selected from the group consisting of H, —CH₃,C_(2to4)alkyl, halogen, hydroxyl, —OCH₃, —OC_(2to4)alkyl, —CF₃, —OCF₃,—NH₂, —CH₂NH₂, —N(CH₃)₂, —NO₂, —CH₂OH, —CO₂CH₃, —CO₂C_(2to4)alkyl,—CO₂H, —N(alkyl)₂ where the two alkyl groups are independently selectedfrom —CH₃ or C_(2to4)alkyl, —NH(alkyl) where the alkyl group is selectedfrom —CH₃ or C_(2to4)alkyl, 4-morpholinyl, 1-piperidinyl,4H-piperazinyl, 4-C_(1to4)alkyl-piperazinyl, and4-C_(3to6)cycloalkyl-piperazinyl, preferably independently selected fromthe group consisting of H, —CH₃, C_(2to4)alkyl, iso-propyl, tert-butyl,halogen wherein halogen is preferably F or Cl or Br, hydroxyl, —OCH₃,—CF₃, —OCF₃, —N(CH₃)₂, —NO₂, and 4-methylpiperazinyl, more preferablyindependently selected from the group consisting of H, —CH₃, —CH₂CH₃,iso-propyl, —N(CH₃)₂, halogen wherein halogen is preferably F or Cl orBr, —OCH₃, —CF₃ and —OCF₃. In a preferred embodiment of the invention atleast two, preferably three or four, of R⁴, R⁵, R⁶, R⁷ and R⁸ are H.

In the compounds comprising the moiety of formulae (I), (IV) and (V) ofthe invention, group A is preferably a moiety selected from the groupcontaining

wherein * and ** are as defined above.

In some embodiments, in the compounds comprising the moiety of formulae(I), (IV) and (V) of the invention, group A is a moiety selected fromthe group containing

wherein * and ** are as defined above.

In some embodiments, in the compounds comprising the moiety of formulae(I), (IV) and (V) of the invention, group A is preferably

wherein * and ** are as defined above.

In the compounds comprising the moiety of formulae (I) and (V) of theinvention, R¹ and R² are preferably independently selected from thegroup consisting of

H, —CH₃, n-propyl, —CH₂N(CH₃)₂, halogen where halogen is preferably Cl,and phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of —CH₃, —CH₂CH₃, —CF₃,—OCF₃, ethynyl, halogen where halogen is preferably F or Cl or Br, and4-halobenzyl where 4-halobenzyl is preferably 4-bromobenzyl, with theprovisos that:when Y is N, R² represents a lone pair of electrons belonging to the Natom; andat least one of R¹ or R² possesses 3 or more carbon atoms; andit is preferred that when R¹ is unsubstituted- or substituted-phenyl, or4-halobenzyl, then when Y is C, R² is H, —CH₃, —CH₂N(CH₃)₂, or halogenwhere halogen is preferably Cl; andit is preferred that when R² is unsubstituted or substituted-phenyl, or4-halobenzyl, R¹ is H, —CH₃, —CH₂N(CH₃)₂, or halogen where halogen ispreferably Cl; andit is preferred that when R¹ is H, R² is not H and that when R² is H, R¹is not H; and it is further preferred that when R¹ is —CH₃, R² is not Hand when R² is —CH₃, R¹ is not H.

In the compounds of the present invention, when one of R¹ or R² ishalogen they are preferably Cl.

In a further embodiment of the invention, the compounds comprising themoiety of formulae (I) and (V) are represented by the formula (VI)

In another embodiment of the invention, the compounds comprising themoiety of formulae (I) and (V) are represented by the formula (VII)

In still another embodiment of the invention, the compounds comprisingthe moiety of formulae (I) and (V) are represented by the formula (VIII)

In another embodiment of the invention, the compounds comprising themoiety of formulae (I) and (V) are represented by the formula (IX)

In another embodiment of the invention, the compounds comprising themoiety of formulae (I) and (V) are represented by the formula (X)

In another embodiment of the invention, the compounds comprising themoiety of formulae (I) and (V) are represented by the formula (XI)

In another embodiment of the invention, the compounds comprising themoiety of formulae (I) and (V) are represented by the formula (XII)

In another embodiment of the invention, the compounds comprising themoiety of formulae (I) and (V) are represented by the formula (XIII)

In another embodiment of the invention, the compounds comprising themoiety of formulae (I) and (V) are represented by the formula (XIV)

In the moieties represented by the formulae (VI) to (XIV), R² isselected from the group consisting of H, —CH₃, C_(2to6)alkyl,C_(3to6)cycloalkyl, halogen, and —(CH₂)_(n)N(CH₃)₂ where n is an integerfrom 1 to 3, preferably selected from the group consisting of H, —CH₃,n-propyl, n-butyl, iso-butyl, —CH₂N(CH₃)₂, and halogen where halogen ispreferably Cl, more preferably selected from the group consisting of H,—CH₃, —CH₂N(CH₃)₂, and halogen where halogen is preferably Cl, R³represents optional substituents on an otherwise unsubstituted phenylring and is preferably one or more substituents independently selectedfrom the group consisting of —CH₃, C_(2to4)alkyl, halogen, hydroxyl,—OCH₃, —OC_(2to4)alkyl, ethynyl, —OCF₃, and —CF₃, more preferably one ormore substituents independently selected from the group consisting of—CH₃, —CH₂CH₃, —OH, —CF₃, —OCF₃, ethynyl, and halogen, wherein halogenis preferably F or Cl or Br, most preferably independently selected fromone or more substituents selected the group consisting of —CH₃, —CH₂CH₃,—CF₃, —OCF₃, ethynyl, and halogen, wherein halogen is preferably F or Clor Br, and R⁴ to R⁸ are independently selected from the group consistingof H, —CH₃, C_(2to4)alkyl, halogen, hydroxyl, —OCH₃, —OC_(2to4)alkyl,—CF₃, —OCF₃, —NH₂, —CH₂NH₂, —N(CH₃)₂, —NO₂, —CH₂OH, —CO₂CH₃,—CO₂C_(2to4)alkyl, —CO₂H, —N(alkyl)₂ where the two alkyl groups areindependently selected from —CH₃ or C_(2to4)alkyl, —NH(alkyl) where thealkyl group is selected from —CH₃ or C_(2to4)alkyl, 4-morpholinyl,1-piperidinyl, 4H-piperazinyl, 4-C_(1to4)alkyl-piperazinyl, and4-C_(3to6)cycloalkyl-piperazinyl, preferably independently selected fromthe group consisting of H, —CH₃, C_(2to4)alkyl, iso-propyl, tert-butyl,halogen wherein halogen is preferably F or Cl or Br, hydroxyl, —OCH₃,—CF₃, —OCF₃, —N(CH₃)₂, —NO₂, 4-methylpiperazinyl, more preferablyindependently selected from the group consisting of H, —CH₃, —CH₂CH₃,iso-propyl, —N(CH₃)₂, halogen wherein halogen is preferably F or Cl orBr, —OCH₃, —CF₃, and —OCF₃, In a preferred embodiment of the inventionat least two, preferably three or, of R⁴, R⁵, R⁶, R⁷ and R⁸ are H.

In some embodiments of the invention, R¹ and R² are independentlyselected from the group consisting of H, —CH₃, —CH₂N(CH₃)₂,4-bromobenzyl, halogen where halogen is preferably Cl, and phenyl, wherephenyl is optionally substituted with one or more substituentsindependently selected from —CH₃, —CH₂CH₃, —CF₃, —OCF₃, ethynyl, andhalogen, wherein halogen is preferably F or Cl or Br.

In some embodiments of the invention, R⁴ to R⁸ are independentlyselected from the group consisting of H, —CH₃, —CH₂CH₃, iso-propyl,—N(CH₃)₂, halogen wherein halogen is preferably F or Cl or Br, —OCH₃,—CF₃, and —OCF₃.

In a preferred embodiment of the invention in which B corresponds to aphenyl ring, at least two, preferably three or four, of R⁴, R⁵, R⁶, R⁷and R⁸ are H.

In some embodiments of the invention, R³ represents optionalsubstituents on an otherwise unsubstituted phenyl ring and is one ormore substituents independently selected from the group consisting of—CH₃, —CH₂CH₃, —CF₃, —OCF₃, ethynyl, and halogen, wherein halogen ispreferably F or Cl or Br.

In some embodiments of the invention, R¹ and R² are independentlyselected from the group consisting of H, —CH₃, —CH₂N(CH₃)₂,4-bromobenzyl, halogen where halogen is preferably Cl, and phenyl, wherephenyl is optionally substituted with one or more substituentsindependently selected from —CH₃, —CH₂CH₃, —CF₃, —OCF₃, ethynyl, andhalogen, wherein halogen is preferably F or Cl or Br, and R⁴ to R⁸ areindependently selected from the group consisting of H, —CH₃, —CH₂CH₃,iso-propyl, —N(CH₃)₂, halogen wherein halogen is preferably F or Cl orBr, —OCH₃, —CF₃, and —OCF₃.

In some embodiments of the present invention, R⁴ to R⁸ are independentlyselected from the group consisting of H, —CH₃, —CH₂CH₃, iso-propyl,—N(CH₃)₂, halogen wherein halogen is preferably F or Cl or Br, —OCH₃,—CF₃ and —OCF₃, and R³ represents optional substituents on an otherwiseunsubstituted phenyl ring and is one or more substituents independentlyselected from the group consisting of —CH₃, —CH₂CH₃, —CF₃, —OCF₃,ethynyl, and halogen wherein halogen is preferably F or Cl or Br.

In any one of the moieties represented by the formulae (IV) or (VI) to(XIV), R² may be a hydrogen atom. In any one of the moieties representedby the formulae (IV) or (VI) to (XIV), R² may be a halogen atom,preferably a chlorine atom. In the moieties represented by the formulae(IV) and (VI) to (VII), R² may be —CH₂N(CH₃)₂. In the moietiesrepresented by the formulae (IV) and (VI) to (XIV), R² is preferably—CH₃.

In any one of the moieties represented by the formulae (VI) to (XIV), R⁴may be as defined for formulae (V). R⁴ may also be selected from thegroup consisting of —CF₃, —OCF₃, —CH₃, —N(CH₃)₂, and halogen. In someembodiments, R⁴ is —CF₃. In other embodiments, R⁴ is —OCF₃. In otherembodiments, R⁴ is —CH₃. In other embodiments, R⁴ is —N(CH₃)₂. In otherembodiments, R⁴ is halogen.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁴ is —CF₃ and each of R⁵ to R⁸ is H. In some embodiments,in the moieties represented by the formulae (V) or (VI) to (XIV) R⁴ is—CF₃ and two of R⁵ to R⁸ are H. In some embodiments, in the moietiesrepresented by the formulae (V) or (VI) to (XIV) R⁴ is —CF₃ and three ofR⁵ to R⁸ are H. In some embodiments represented by the formulae (VI) to(XIV), R⁴ is —CF₃, and R² is —CH₃. In other embodiments represented bythe formulae (VI) to (XIV), R⁴ is —CF₃, and R² is a hydrogen atom. Inother embodiments represented by the formulae (VI) to (XIV), R⁴ is —CF₃,and R² is halogen. In some embodiments represented by the formulae (VI)to (XIV), R⁴ is —CF₃, each of R⁵ to R⁸ is H and R² is —CH₃. In someembodiments represented by the formulae (VI) to (XIV), R⁴ is —CF₃, twoof R⁵ to R⁸ are H and R² is —CH₃. In some embodiments represented by theformulae (VI) to (XIV), R⁴ is —CF₃, three of R⁵ to R⁸ are H and R² is—CH₃. In other embodiments represented by the formulae (VI) to (XIV), R⁴is —CF₃, each of R⁵ to R⁸ is H and R² is a hydrogen atom. In someembodiments represented by the formulae (VI) to (XIV), R⁴ is —CF₃, twoof R⁵ to R⁸ are H and R² is a hydrogen atom. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁴ is —CF₃, three of R⁵ to R⁸are H and R² is a hydrogen atom. In other embodiments represented by theformulae (VI) to (XIV), R⁴ is —CF₃, each of R⁵ to R⁸ is H and R² ishalogen. In some embodiments represented by the formulae (VI) to (XIV),R⁴ is —CF₃, two of R⁵ to R⁸ are H and R² is halogen. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁴ is —CF₃, three of R⁵ to R⁸are H and R² is halogen. In the formulae (VI) to (XIV), when R⁴ is —CF₃,and R² is halogen, R² is preferably Cl.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁴ is —OCF₃ and each of R⁵ to R⁸ is H. In someembodiments, in the moieties represented by the formulae (V) or (VI) to(XIV) R⁴ is —OCF₃ and two of R⁵ to R⁸ are H. In some embodiments, in themoieties represented by the formulae (V) or (VI) to (XIV) R⁴ is —OCF₃and three of R⁵ to R⁸ are H. In some embodiments represented by theformulae (VI) to (XIV), R⁴ is —OCF₃, and R² is —CH₃. In otherembodiments represented by the formulae (VI) to (XIV), R⁴ is —OCF₃, andR² is a hydrogen atom. In other embodiments represented by the formulae(VI) to (XIV), R⁴ is —OCF₃, and R² is halogen. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁴ is —OCF₃, each of R⁵ to R⁸is H and R² is —CH₃. In some embodiments represented by the formulae(VI) to (XIV), R⁴ is —OCF₃, two of R⁵ to R⁸ are H and R² is —CH₃. Insome embodiments represented by the formulae (VI) to (XIV), R⁴ is —OCF₃,three of R⁵ to R⁸ are H and R² is —CH₃. In other embodiments representedby the formulae (VI) to (XIV), R⁴ is —OCF₃, each of R⁵ to R⁸ is H and R²is a hydrogen atom. In some embodiments represented by the formulae (VI)to (XIV), R⁴ is —OCF₃, two of R⁵ to R⁸ are H and R² is a hydrogen atom.In some embodiments represented by the formulae (VI) to (XIV), R⁴ is—OCF₃, three of R⁵ to R⁸ are H and R² is a hydrogen atom. In otherembodiments represented by the formulae (VI) to (XIV), R⁴ is —OCF₃, eachof R⁵ to R⁸ is H and R² is halogen. In some embodiments represented bythe formulae (VI) to (XIV), R⁴ is —OCF₃, two of R⁵ to R⁸ are H and R² ishalogen. In some embodiments represented by the formulae (VI) to (XIV),R⁴ is —OCF₃, three of R⁵ to R⁸ are H and R² is halogen. In the formulae(VI) to (XIV), when R⁴ is —OCF₃, and R² is halogen, R² is preferably Cl.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁴ is —CH₃ and each of R⁵ to R⁸ is H. In some embodiments,in the moieties represented by the formulae (V) or (VI) to (XIV) R⁴ is—CH₃ and two of R⁵ to R⁸ are H. In some embodiments, in the moietiesrepresented by the formulae (V) or (VI) to (XIV) R⁴ is —CH₃ and three ofR⁵ to R⁸ are H. In some embodiments represented by the formulae (VI) to(XIV), R⁴ is —CH₃, and R² is —CH₃. In other embodiments represented bythe formulae (VI) to (XIV), R⁴ is —CH₃, and R² is a hydrogen atom. Inother embodiments represented by the formulae (VI) to (XIV), R⁴ is —CH₃,and R² is halogen. In some embodiments represented by the formulae (VI)to (XIV), R⁴ is —CH₃, each of R⁵ to R⁸ is H and R² is —CH₃. In someembodiments represented by the formulae (VI) to (XIV), R⁴ is —CH₃, twoof R⁵ to R⁸ are H and R² is —CH₃. In some embodiments represented by theformulae (VI) to (XIV), R⁴ is —CH₃, three of R⁵ to R⁸ are H and R² is—CH₃. In other embodiments represented by the formulae (VI) to (XIV), R⁴is —CH₃, each of R⁵ to R⁸ is H and R² is a hydrogen atom. In someembodiments represented by the formulae (VI) to (XIV), R⁴ is —CH₃, twoof R⁵ to R⁸ are H and R² is a hydrogen atom. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁴ is —CH₃, three of R⁵ to R⁸are H and R² is a hydrogen atom. In other embodiments represented by theformulae (VI) to (XIV), R⁴ is —CH₃, each of R⁵ to R⁸ is H and R² ishalogen. In some embodiments represented by the formulae (VI) to (XIV),R⁴ is —CH₃, two of R⁵ to R⁸ are H and R² is halogen. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁴ is —CH₃, three of R⁵ to R⁸are H and R² is halogen. In the formulae (VI) to (XIV), when R⁴ is —CH₃,and R² is halogen, R² is preferably Cl.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁴ is —N(CH₃)₂ and each of R⁵ to R⁸ is H. In someembodiments, in the moieties represented by the formulae (V) or (VI) to(XIV) R⁴ is —N(CH₃)₂ and two of R⁵ to R⁸ are H. In some embodiments, inthe moieties represented by the formulae (V) or (VI) to (XIV) R⁴ is—N(CH₃)₂ and three of R⁵ to R⁸ are H. In some embodiments represented bythe formulae (VI) to (XIV), R⁴ is —N(CH₃)₂, and R² is —CH₃. In otherembodiments represented by the formulae (VI) to (XIV), R⁴ is —N(CH₃)₂,and R² is a hydrogen atom. In other embodiments represented by theformulae (VI) to (XIV), R⁴ is —N(CH₃)₂, and R² is halogen. In someembodiments represented by the formulae (VI) to (XIV), R⁴ is —N(CH₃)₂,each of R⁵ to R⁸ is H and R² is —CH₃. In some embodiments represented bythe formulae (VI) to (XIV), R⁴ is —N(CH₃)₂, two of R⁵ to R⁸ are H and R²is —CH₃. In some embodiments represented by the formulae (VI) to (XIV),R⁴ is —N(CH₃)₂, three of R⁵ to R⁸ are H and R² is —CH₃. In otherembodiments represented by the formulae (VI) to (XIV), R⁴ is —N(CH₃)₂,each of R⁵ to R⁸ is H and R² is a hydrogen atom. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁴ is —N(CH₃)₂, two of R⁵ toR⁸ are H and R² is a hydrogen atom. In some embodiments represented bythe formulae (VI) to (XIV), R⁴ is —N(CH₃)₂, three of R⁵ to R⁸ are H andR² is a hydrogen atom. In other embodiments represented by the formulae(VI) to (XIV), R⁴ is —N(CH₃)₂, each of R⁵ to R⁸ is H and R² is halogen.In some embodiments represented by the formulae (VI) to (XIV), R⁴ is—N(CH₃)₂, two of R⁵ to R⁸ are H and R² is halogen. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁴ is —N(CH₃)₂, three of R⁵to R⁸ are H and R² is halogen. In the formulae (VI) to (XIV), when R⁴ is—N(CH₃)₂, and R² is halogen, R² is preferably Cl.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁴ is halogen and each of R⁵ to R⁸ is H. In someembodiments, in the moieties represented by the formulae (V) or (VI) to(XIV) R⁴ is halogen and two of R⁵ to R⁸ are H. In some embodiments, inthe moieties represented by the formulae (V) or (VI) to (XIV) R⁴ ishalogen and three of R⁵ to R⁸ are H. In some embodiments represented bythe formulae (VI) to (XIV), R⁴ is halogen, and R² is —CH₃. In otherembodiments represented by the formulae (VI) to (XIV), R⁴ is halogen,and R² is a hydrogen atom. In other embodiments represented by theformulae (VI) to (XIV), R⁴ is halogen, and R² is halogen. In someembodiments represented by the formulae (VI) to (XIV), R⁴ is halogen,each of R⁵ to R⁸ is H and R² is —CH₃. In some embodiments represented bythe formulae (VI) to (XIV), R⁴ is halogen, two of R⁵ to R⁸ are H and R²is —CH₃. In some embodiments represented by the formulae (VI) to (XIV),R⁴ is halogen, three of R⁵ to R⁸ are H and R² is —CH₃. In otherembodiments represented by the formulae (VI) to (XIV), R⁴ is halogen,each of R⁵ to R⁸ is H and R² is a hydrogen atom. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁴ is halogen, two of R⁵ toR⁸ are H and R² is a hydrogen atom. In some embodiments represented bythe formulae (VI) to (XIV), R⁴ is halogen, three of R⁵ to R⁸ are H andR² is a hydrogen atom. In other embodiments represented by the formulae(VI) to (XIV), R⁴ is halogen, each of R⁵ to R⁸ is H and R² is halogen.In some embodiments represented by the formulae (VI) to (XIV), R⁴ ishalogen, two of R⁵ to R⁸ are H and R² is halogen. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁴ is halogen, three of R⁵ toR⁸ are H and R² is halogen. In some embodiments where R⁴ is halogen, R⁴is chlorine. In some embodiments where R⁴ is halogen, R⁴ is fluorine. Insome embodiments where R⁴ is halogen, R⁴ is bromine. When R⁴ is halogen,R⁴ is preferably F, more preferably Cl. In the formulae (VI) to (XIV),when R⁴ is halogen, and R² is halogen, R² is preferably Cl.

In any one of the moieties represented by the formulae (VI) to (XIV), R⁵may be as defined for formulae (V). R⁵ may also be selected from thegroup consisting of —CF₃, —OCF₃, and halogen. In some embodiments, R⁵ is—CF₃. In some embodiments, R⁵ is —OCF₃. In some embodiments, R⁵ ishalogen.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁵ is —CF₃ and each of R⁴ and R⁶ to R⁸ is H. In someembodiments, in the moieties represented by the formulae (V) or (VI) to(XIV) R⁵ is —CF₃ and two of R⁴ and R⁶ to R⁸ are H. In some embodiments,in the moieties represented by the formulae (V) or (VI) to (XIV) R⁵ is—CF₃ and three of R⁴ and R⁶ to R⁸ are H. In some embodiments representedby the formulae (VI) to (XIV), R⁵ is —CF₃, and R² is —CH₃. In otherembodiments represented by the formulae (VI) to (XIV), R⁵ is —CF₃, andR² is a hydrogen atom. In other embodiments represented by the formulae(VI) to (XIV), R⁵ is —CF₃, and R² is halogen. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁵ is —CF₃, each of R⁴ and R⁶to R⁸ is H, and R² is —CH₃. In some embodiments represented by theformulae (VI) to (XIV), R⁵ is —CF₃, two of R⁴ and R⁶ to R⁸ are H, and R²is —CH₃. In some embodiments represented by the formulae (VI) to (XIV),R⁵ is —CF₃, three of R⁴ and R⁶ to R⁸ are H, and R² is —CH₃. In otherembodiments represented by the formulae (VI) to (XIV), R⁵ is —CF₃, eachof R⁴ and R⁶ to R⁸ is H, and R² is a hydrogen atom. In other embodimentsrepresented by the formulae (VI) to (XIV), R⁵ is —CF₃, two of R⁴ and R⁶to R⁸ are H, and R² is a hydrogen atom. In other embodiments representedby the formulae (VI) to (XIV), R⁵ is —CF₃, three of R⁴ and R⁶ to R⁸ areH, and R² is a hydrogen atom. In other embodiments represented by theformulae (VI) to (XIV), R⁵ is —CF₃, each of R⁴ and R⁶ to R⁸ is H, and R²is halogen. In other embodiments represented by the formulae (VI) to(XIV), R⁵ is —CF₃, two of R⁴ and R⁶ to R⁸ are H, and R² is halogen. Inother embodiments represented by the formulae (VI) to (XIV), R⁵ is —CF₃,three of R⁴ and R⁶ to R⁸ are H, and R² is halogen. In the formulae (VI)to (XIV), when R⁵ is —CF₃, and R² is halogen, R² is preferably Cl.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁵ is —OCF₃ and each of R⁴ and R⁶ to R⁸ is H. In someembodiments, in the moieties represented by the formulae (V) or (VI) to(XIV) R⁵ is —OCF₃ and two of R⁴ and R⁶ to R⁸ are H. In some embodiments,in the moieties represented by the formulae (V) or (VI) to (XIV) R⁵ is—OCF₃ and three of R⁴ and R⁶ to R⁸ are H. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁵ is —OCF₃, and R² is —CH₃.In other embodiments represented by the formulae (VI) to (XIV), R⁵ is—OCF₃, and R² is a hydrogen atom. In other embodiments represented bythe formulae (VI) to (XIV), R⁵ is —OCF₃, and R² is halogen. In someembodiments represented by the formulae (VI) to (XIV), R⁵ is —OCF₃, eachof R⁴ and R⁶ to R⁸ is H, and R² is —CH₃. In some embodiments representedby the formulae (VI) to (XIV), R⁵ is —OCF₃, two of R⁴ and R⁶ to R⁸ areH, and R² is —CH₃. In some embodiments represented by the formulae (VI)to (XIV), R⁵ is —OCF₃, three of R⁴ and R⁶ to R⁸ are H, and R² is —CH₃.In other embodiments represented by the formulae (VI) to (XIV), R⁵ is—OCF₃, each of R⁴ and R⁶ to R⁸ is H, and R² is a hydrogen atom. In otherembodiments represented by the formulae (VI) to (XIV), R⁵ is —OCF₃, twoof R⁴ and R⁶ to R⁸ are H, and R² is a hydrogen atom. In otherembodiments represented by the formulae (VI) to (XIV), R⁵ is —OCF₃,three of R⁴ and R⁶ to R⁸ are H, and R² is a hydrogen atom. In otherembodiments represented by the formulae (VI) to (XIV), R⁵ is —OCF₃, eachof R⁴ and R⁶ to R⁸ is H, and R² is halogen. In other embodimentsrepresented by the formulae (VI) to (XIV), R⁵ is —OCF₃, two of R⁴ and R⁶to R⁸ are H, and R² is halogen. In other embodiments represented by theformulae (VI) to (XIV), R⁵ is —OCF₃, three of R⁴ and R⁶ to R⁸ are H, andR² is halogen. In the formulae (VI) to (XIV), when R⁵ is —OCF₃, and R²is halogen, R² is preferably Cl.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁵ is halogen and each of R⁴ and R⁶ to R⁸ is H. In someembodiments, in the moieties represented by the formulae (V) or (VI) to(XIV) R⁵ is halogen and two of R⁴ and R⁶ to R⁸ are H. In someembodiments, in the moieties represented by the formulae (V) or (VI) to(XIV) R⁵ is halogen and three of R⁴ and R⁶ to R⁸ are H. In someembodiments represented by the formulae (VI) to (XIV), R⁵ is halogen,and R² is —CH₃. In other embodiments represented by the formulae (VI) to(XIV), R⁵ is halogen, and R² is a hydrogen atom. In other embodimentsrepresented by the formulae (VI) to (XIV), R⁵ is halogen, and R² ishalogen. In some embodiments represented by the formulae (VI) to (XIV),R⁵ is halogen, each of R⁴ and R⁶ to R⁸ is H, and R² is —CH₃. In someembodiments represented by the formulae (VI) to (XIV), R⁵ is halogen,two of R⁴ and R⁶ to R⁸ are H, and R² is —CH₃. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁵ is halogen, three of R⁴and R⁶ to R⁸ are H, and R² is —CH₃. In other embodiments represented bythe formulae (VI) to (XIV), R⁵ is halogen, each of R⁴ and R⁶ to R⁸ is H,and R² is a hydrogen atom. In other embodiments represented by theformulae (VI) to (XIV), R⁵ is halogen, two of R⁴ and R⁶ to R⁸ are H, andR² is a hydrogen atom. In other embodiments represented by the formulae(VI) to (XIV), R⁵ is halogen, three of R⁴ and R⁶ to R⁸ are H, and R² isa hydrogen atom. In other embodiments represented by the formulae (VI)to (XIV), R⁵ is halogen, each of R⁴ and R⁶ to R⁸ is H, and R² ishalogen. In other embodiments represented by the formulae (VI) to (XIV),R⁵ is halogen, two of R⁴ and R⁶ to R⁸ are H, and R² is halogen. In otherembodiments represented by the formulae (VI) to (XIV), R⁵ is halogen,three of R⁴ and R⁶ to R⁸ are H, and R² is halogen. In some embodimentswhere R⁵ is halogen, R⁵ is chlorine. In some embodiments where R⁵ ishalogen, R⁵ is fluorine. In some embodiments where R⁵ is halogen, R⁵ isbromine. When R⁵ is halogen, R⁵ is preferably F, more preferably Cl. Inthe formulae (VI) to (XIV), when R⁵ is halogen, and R² is halogen, R² ispreferably Cl.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁶ is halogen. In some embodiments represented by theformulae (V) or (VI) to (XIV), R⁶ is halogen and each of R⁴, R⁵, R⁷ andR⁸ is H. In some embodiments represented by the formulae (V) or (VI) to(XIV), R⁶ is halogen and two of R⁴, R⁵, R⁷ and R⁸ are H. In someembodiments represented by the formulae (V) or (VI) to (XIV), R⁶ ishalogen and three of R⁴, R⁵, R⁷ and R⁸ are H. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is halogen, and R² is—CH₃. In other embodiments represented by the formulae (VI) to (XIV), R⁶is halogen, and R² is a hydrogen atom. In other embodiments representedby the formulae (VI) to (XIV), R⁶ is halogen, and R² is halogen. In someembodiments represented by the formulae (VI) to (XIV), R⁶ is halogen,each of R⁴, R⁵, R⁷ and R⁸ is H, and R² is —CH₃. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is halogen, two of R⁴, R⁵,R⁷ and R⁸ are H, and R² is —CH₃. In some embodiments represented by theformulae (VI) to (XIV), R⁶ is halogen, three of R⁴, R⁵, R⁷ and R⁸ are H,and R² is —CH₃. In other embodiments represented by the formulae (VI) to(XIV), R⁶ is halogen, each of R⁴, R⁵, R⁷ and R⁸ is H, and R² is ahydrogen atom. In other embodiments represented by the formulae (VI) to(XIV), R⁶ is halogen, two of R⁴, R⁵, R⁷ and R⁸ are H, and R² is ahydrogen atom. In other embodiments represented by the formulae (VI) to(XIV), R⁶ is halogen, three of R⁴, R⁵, R⁷ and R⁸ are H, and R² is ahydrogen atom. In other embodiments represented by the formulae (VI) to(XIV), R⁶ is halogen, each of R⁴, R⁵, R⁷ and R⁸ is H, and R² is halogen.In other embodiments represented by the formulae (VI) to (XIV), R⁶ ishalogen, two of R⁴, R⁵, R⁷ and R⁸ are H, and R² is halogen. In otherembodiments represented by the formulae (VI) to (XIV), R⁶ is halogen,three of R⁴, R⁵, R⁷ and R⁸ are H, and R² is halogen. In some embodimentswhere R⁶ is halogen, R⁶ is chlorine. In some embodiments where R⁶ ishalogen, R⁶ is fluorine. In some embodiments where R⁶ is halogen, R⁶ isbromine. When R⁶ is halogen, R⁶ is preferably F, more preferably Cl. Inthe formulae (VI) to (XIV), when R⁶ is halogen, and R² is halogen, R² ispreferably Cl.

In some embodiments, in the moieties represented by the formula (V) or(VI) to (XIV) R⁶ is —OCH₃ or —OC_(2to4)alkyl. In some embodimentsmoieties represented by the formula (V) or (VI) to (XIV), R⁶ is —OCH₃ or—OC_(2to4)alkyl and each of R⁴ and R⁶ to R⁸ is H. In some embodimentsrepresented by the formulae (V) or (VI) to (XIV), R⁶ is —OCH₃ or—OC_(2to4)alkyl and two of R⁴, R⁵, R⁷ and R⁸ are H. In some embodimentsrepresented by the formulae (V) or (VI) to (XIV), R⁶ is —OCH₃ or—OC_(2to4)alkyl and three of R⁴, R⁵, R⁷ and R⁸ are H. In someembodiments represented by the formulae (VI) to (XIV), R⁶ is —OCH₃ or—OC_(2to4)alkyl, and R² is —CH₃. In other embodiments represented by theformulae (VI) to (XIV) R⁶ is —OCH₃ or —OC_(2to4)alkyl, and R² is ahydrogen atom. In other embodiments represented by the formulae (VI) to(XIV), R⁶ is —OCH₃ or —OC_(2to4)alkyl, and R² is halogen. In someembodiments represented by the formulae (VI) to (XIV), R⁶ is —OCH₃ or—OC_(2to4)alkyl, each of R⁴ and R⁶ to R⁸ is H, and R² is —CH₃. In someembodiments represented by the formulae (VI) to (XIV), R⁶ is —OCH₃ or—OC_(2to4)alkyl, two of R⁴, R⁵, R⁷ and R⁸ are H, and R² is —CH₃. In someembodiments represented by the formulae (VI) to (XIV), R⁶ is —OCH₃ or—OC_(2to4)alkyl, three of R⁴, R⁵, R⁷ and R⁸ are H, and R² is —CH₃. Inother embodiments represented by the formulae (VI) to (XIV), R⁶ is —OCH₃or —OC_(2to4)alkyl, each of R⁴ and R⁶ to R⁸ is H, and R² is a hydrogenatom. In other embodiments represented by the formulae (VI) to (XIV), R⁶is —OCH₃ or —OC_(2to4)alkyl, two of R⁴, R⁵, R⁷ and R⁸ are H, and R² is ahydrogen atom. In other embodiments represented by the formulae (VI) to(XIV), R⁶ is —OCH₃ or —OC_(2to4)alkyl, three of R⁴, R⁵, R⁷ and R⁸ are H,and R² is a hydrogen atom. In other embodiments represented by theformulae (VI) to (XIV), R⁶ is —OCH₃ or —OC_(2to4)alkyl, each of R⁴ andR⁶ to R⁸ is H, and R² is halogen. In other embodiments represented bythe formulae (VI) to (XIV), R⁶ is —OCH₃ or —OC_(2to4)alkyl, two of R⁴,R⁵, R⁷ and R⁸ are H, and R² is halogen. In other embodiments representedby the formulae (VI) to (XIV), R⁶ is —OCH₃ or —OC_(2to4)alkyl, three ofR⁴, R⁵, R⁷ and R⁸ are H, and R² is halogen. When R⁶ is —OCH₃ or—OC_(2to4)alkyl, R⁶ is preferably —OCH₃. In the formulae (VI) to (XIV),when R⁶ is —OCH₃ or —OC_(2to4)alkyl, and R² is halogen, R² is preferablyCl.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁶ is —CF₃. In some embodiments represented by theformulae (V) or (VI) to (XIV), R⁶ is —CF₃ and each of R⁴, R⁵, R⁷ and R⁸is H. In some embodiments represented by the formulae (V) or (VI) to(XIV), R⁶ is —CF₃ and two of R⁴, R⁵, R⁷ and R⁸ are H. In someembodiments represented by the formulae (V) or (VI) to (XIV), R⁶ is —CF₃and three of R⁴, R⁵, R⁷ and R⁸ are H. In some embodiments represented bythe formulae (VI) to (XIV), R⁶ is —CF₃, and R² is —CH₃. In otherembodiments represented by the formulae (VI) to (XIV), R⁶ is —CF₃, andR² is a hydrogen atom. In other embodiments represented by the formulae(VI) to (XIV), R⁶ is —CF₃, and R² is halogen. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is —CF₃, each of R⁴, R⁵,R⁷ and R⁸ is H, and R² is —CH₃. In some embodiments represented by theformulae (VI) to (XIV), R⁶ is —CF₃, two of R⁴, R⁵, R⁷ and R⁸ are H, andR² is —CH₃. In some embodiments represented by the formulae (VI) to(XIV), R⁶ is —CF₃, three of R⁴, R⁵, R⁷ and R⁸ are H, and R² is —CH₃. Inother embodiments represented by the formulae (VI) to (XIV), R⁶ is —CF₃,each of R⁴, R⁵, R⁷ and R⁸ is H, and R² is a hydrogen atom. In otherembodiments represented by the formulae (VI) to (XIV), R⁶ is —CF₃, twoof R⁴, R⁵, R⁷ and R⁸ are H, and R² is a hydrogen atom. In otherembodiments represented by the formulae (VI) to (XIV), R⁶ is —CF₃, threeof R⁴, R⁵, R⁷ and R⁸ are H, and R² is a hydrogen atom. In otherembodiments represented by the formulae (VI) to (XIV), R⁶ is —CF₃, eachof R⁴, R⁵, R⁷ and R⁸ is H, and R² is halogen. In other embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is —CF₃, two of R⁴, R⁵, R⁷and R⁸ are H, and R² is halogen. In other embodiments represented by theformulae (VI) to (XIV), R⁶ is —CF₃, three of R⁴, R⁵, R⁷ and R⁸ are H,and R² is halogen. In the formulae (VI) to (XIV), when R⁶ is —CF₃, andR² is halogen, R² is preferably Cl.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁶ is —CH₃. In some embodiments represented by theformulae (V) or (VI) to (XIV), R⁶ is —CH₃ and each of R⁴, R⁵, R⁷ and R⁸is H. In some embodiments represented by the formulae (V) or (VI) to(XIV), R⁶ is —CH₃ and two of R⁴, R⁵, R⁷ and R⁸ are H. In someembodiments represented by the formulae (V) or (VI) to (XIV), R⁶ is —CH₃and three of R⁴, R⁵, R⁷ and R⁸ are H. In some embodiments represented bythe formulae (VI) to (XIV), R⁶ is —CH₃, and R² is —CH₃. In otherembodiments represented by the formulae (VI) to (XIV), R⁶ is —CH₃, andR² is a hydrogen atom. In other embodiments represented by the formulae(VI) to (XIV), R⁶ is —CH₃, and R² is halogen. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is —CH₃, each of R⁴, R⁵,R⁷ and R⁸ is H, and R² is —CH₃. In some embodiments represented by theformulae (VI) to (XIV), R⁶ is —CH₃, two of R⁴, R⁵, R⁷ and R⁸ are H, andR² is —CH₃. In some embodiments represented by the formulae (VI) to(XIV), R⁶ is —CH₃, three of R⁴, R⁵, R⁷ and R⁸ are H, and R² is —CH₃. Inother embodiments represented by the formulae (VI) to (XIV), R⁶ is —CH₃,each of R⁴, R⁵, R⁷ and R⁸ is H, and R² is a hydrogen atom. In otherembodiments represented by the formulae (VI) to (XIV), R⁶ is —CH₃, twoof R⁴, R⁵, R⁷ and R⁸ are H, and R² is a hydrogen atom. In otherembodiments represented by the formulae (VI) to (XIV), R⁶ is —CH₃, threeof R⁴, R⁵, R⁷ and R⁸ are H, and R² is a hydrogen atom. In otherembodiments represented by the formulae (VI) to (XIV), R⁶ is —CH₃, eachof R⁴, R⁵, R⁷ and R⁸ is H, and R² is halogen. In other embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is —CH₃, two of R⁴, R⁵, R⁷and R⁸ are H, and R² is halogen. In other embodiments represented by theformulae (VI) to (XIV), R⁶ is —CH₃, three of R⁴, R⁵, R⁷ and R⁸ are H,and R² is halogen. In the formulae (VI) to (XIV), when R⁶ is —CH₃, andR² is halogen, R² is preferably Cl.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁶ is —OCF₃. In some embodiments represented by theformulae (V) or (VI) to (XIV), R⁶ is —OCF₃ and each of R⁴, R⁵, R⁷ and R⁸is H. In some embodiments represented by the formulae (V) or (VI) to(XIV), R⁶ is —OCF₃ and two of R⁴, R⁵, R⁷ and R⁸ are H. In someembodiments represented by the formulae (V) or (VI) to (XIV), R⁶ is—OCF₃ and three of R⁴, R⁵, R⁷ and R⁸ are H. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is —OCF₃, and R² is —CH₃.In other embodiments represented by the formulae (VI) to (XIV), R⁶ is—OCF₃, and R² is a hydrogen atom. In other embodiments represented bythe formulae (VI) to (XIV), R⁶ is —OCF₃, and R² is halogen. In someembodiments represented by the formulae (VI) to (XIV), R⁶ is —OCF₃, eachof R⁴, R⁵, R⁷ and R⁸ is H, and R² is —CH₃. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is —OCF₃, two of R⁴, R⁵,R⁷ and R⁸ are H, and R² is —CH₃. In some embodiments represented by theformulae (VI) to (XIV), R⁶ is —OCF₃, three of R⁴, R⁵, R⁷ and R⁸ are H,and R² is —CH₃. In other embodiments represented by the formulae (VI) to(XIV), R⁶ is —OCF₃, each of R⁴, R⁵, R⁷ and R⁸ is H, and R² is a hydrogenatom. In other embodiments represented by the formulae (VI) to (XIV), R⁶is —OCF₃, two of R⁴, R⁵, R⁷ and R⁸ are H, and R² is a hydrogen atom. Inother embodiments represented by the formulae (VI) to (XIV), R⁶ is—OCF₃, three of R⁴, R⁵, R⁷ and R⁸ are H, and R² is a hydrogen atom. Inother embodiments represented by the formulae (VI) to (XIV), R⁶ is—OCF₃, each of R⁴, R⁵, R⁷ and R⁸ is H, and R² is halogen. In otherembodiments represented by the formulae (VI) to (XIV), R⁶ is —OCF₃, twoof R⁴, R⁵, R⁷ and R⁸ are H, and R² is halogen. In other embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is —OCF₃, three of R⁴, R⁵,R⁷ and R⁸ are H, and R² is halogen. In the formulae (VI) to (XIV), whenR⁶ is —OCF₃, and R² is halogen, R² is preferably Cl.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁶ is ethyl. In some embodiments represented by theformulae (V) or (VI) to (XIV), R⁶ is ethyl and each of R⁴, R⁵, R⁷ and R⁸is H. In some embodiments represented by the formulae (V) or (VI) to(XIV), R⁶ is ethyl and two of R⁴, R⁵, R⁷ and R⁸ are H. In someembodiments represented by the formulae (V) or (VI) to (XIV), R⁶ isethyl and three of R⁴, R⁵, R⁷ and R⁸ are H. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is ethyl, and R² is —CH₃.In other embodiments represented by the formulae (VI) to (XIV), R⁶ isethyl, and R² is a hydrogen atom. In other embodiments represented bythe formulae (VI) to (XIV), R⁶ is ethyl, and R² is halogen. In someembodiments represented by the formulae (VI) to (XIV), R⁶ is ethyl, eachof R⁴, R⁵, R⁷ and R⁸ is H, and R² is —CH₃. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is ethyl, two of R⁴, R⁵,R⁷ and R⁸ are H, and R² is —CH₃. In some embodiments represented by theformulae (VI) to (XIV), R⁶ is ethyl, three of R⁴, R⁵, R⁷ and R⁸ are H,and R² is —CH₃. In other embodiments represented by the formulae (VI) to(XIV), R⁶ is ethyl, each of R⁴, R⁵, R⁷ and R⁸ is H, and R² is a hydrogenatom. In other embodiments represented by the formulae (VI) to (XIV), R⁶is ethyl, two of R⁴, R⁵, R⁷ and R⁸ are H, and R² is a hydrogen atom. Inother embodiments represented by the formulae (VI) to (XIV), R⁶ isethyl, three of R⁴, R⁵, R⁷ and R⁸ are H, and R² is a hydrogen atom. Inother embodiments represented by the formulae (VI) to (XIV), R⁶ isethyl, each of R⁴, R⁵, R⁷ and R⁸ is H, and R² is halogen. In otherembodiments represented by the formulae (VI) to (XIV), R⁶ is ethyl, twoof R⁴, R⁵, R⁷ and R⁸ are H, and R² is halogen. In other embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is ethyl, three of R⁴, R⁵,R⁷ and R⁸ are H, and R² is halogen. In the formulae (VI) to (XIV), whenR⁶ is ethyl, and R² is halogen, R² is preferably Cl.

In some embodiments, in the moieties represented by the formulae (V) or(VI) to (XIV) R⁶ is iso-propyl. In some embodiments represented by theformulae (V) or (VI) to (XIV), R⁶ is iso-propyl and each of R⁴, R⁵, R⁷and R⁸ is H. In some embodiments represented by the formulae (V) or (VI)to (XIV), R⁶ is iso-propyl and two of R⁴, R⁵, R⁷ and R⁸ are H. In someembodiments represented by the formulae (V) or (VI) to (XIV), R⁶ isiso-propyl and three of R⁴, R⁵, R⁷ and R⁸ are H. In some embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is iso-propyl, and R² is—CH₃. In other embodiments represented by the formulae (VI) to (XIV), R⁶is iso-propyl, and R² is a hydrogen atom. In other embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is iso-propyl, and R² ishalogen. In some embodiments represented by the formulae (VI) to (XIV),R⁶ is iso-propyl, each of R⁴, R⁵, R⁷ and R⁸ is H, and R² is —CH₃. Insome embodiments represented by the formulae (VI) to (XIV), R⁶ isiso-propyl, two of R⁴, R⁵, R⁷ and R⁸ are H, and R² is —CH₃. In someembodiments represented by the formulae (VI) to (XIV), R⁶ is iso-propyl,three of R⁴, R⁵, R⁷ and R⁸ are H, and R² is —CH₃. In other embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is iso-propyl, each of R⁴,R⁵, R⁷ and R⁸ is H, and R² is a hydrogen atom. In other embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is iso-propyl, two of R⁴,R⁵, R⁷ and R⁸ are H, and R² is a hydrogen atom. In other embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is iso-propyl, three ofR⁴, R⁵, R⁷ and R⁸ are H, and R² is a hydrogen atom. In other embodimentsrepresented by the formulae (VI) to (XIV), R⁶ is iso-propyl, each of R⁴,R⁵, R⁷ and R⁸ is H, and R² is halogen. In other embodiments representedby the formulae (VI) to (XIV), R⁶ is iso-propyl, two of R⁴, R⁵, R⁷ andR⁸ are H, and R² is halogen. In other embodiments represented by theformulae (VI) to (XIV), R⁶ is iso-propyl, three of R⁴, R⁵, R⁷ and R⁸ areH, and R² is halogen. In the formulae (VI) to (XIV), when R⁶ isiso-propyl, and R² is halogen, R² is preferably Cl.

In some embodiments of the present invention, all of R⁴ to R⁸ arehydrogen. In some embodiments of the present invention, only R⁴ is nothydrogen. In some embodiments of the present invention, only R⁵ is nothydrogen. In some embodiments of the present invention, only R⁶ is nothydrogen. In the moieties of the compounds of the present invention,more than one of R⁴ to R⁸ may be a group other than hydrogen. In someembodiments, when more than one of R⁴ to R⁸ is a group other thanhydrogen in the moieties of the compounds of the present invention, itis preferred that two of R⁴ to R⁸ are a group other than hydrogen. Insome embodiments, R⁴ and R⁵ are groups other than hydrogen. In someembodiments, R⁴ and R⁵ are groups other than hydrogen and R⁶ to R⁸ arehydrogen. In some embodiments, R⁴ and R⁶ are groups other than hydrogen.In some embodiments, R⁴ and R⁶ are groups other than hydrogen and R⁵, R⁷and R⁸ are hydrogen. In some embodiments, R⁴ and R⁷ are groups otherthan hydrogen. In some embodiments, R⁴ and R⁷ are groups other thanhydrogen and R⁵, R⁶ and R⁸ are hydrogen. In some embodiments, R⁴ and R⁸are groups other than hydrogen. In some embodiments, R⁴ and R⁸ aregroups other than hydrogen and R⁵, R⁶ and R⁷ are hydrogen. In someembodiments, R⁵ and R⁶ are groups other than hydrogen. In someembodiments, R⁵ and R⁶ are groups other than hydrogen and R⁴, R⁷ and R⁸are hydrogen. Particularly preferred is when R⁴ and R⁶ are groups otherthan hydrogen and R⁵, R⁷ and R⁸ are hydrogen, still more preferred R⁵and R⁶ are groups other than hydrogen and R⁴, R⁷ and R⁸ are hydrogen. Ina preferred embodiment of the invention at least two, preferably threeor four, of R⁴, R⁵, R⁶, R⁷ and R⁸ are H.

In some embodiments, when two of R⁴ to R⁸ are a group other thanhydrogen in the moieties of the compounds of the present invention, R⁵is CF₃ and R⁶ is Cl. In some embodiments, when two of R⁴ to R⁸ are agroup other than hydrogen in the moieties of the compounds of thepresent invention, R⁵ is OCF₃ and R⁶ is Cl. In some embodiments, whentwo of R⁴ to R⁸ are a group other than hydrogen in the moieties of thecompounds of the present invention, R⁶ is CF₃ and R⁵ is Cl. In someembodiments, when two of R⁴ to R⁸ are a group other than hydrogen in themoieties of the compounds of the present invention, R⁶ is OCF₃ and R⁵ isCl. These specific substitution combinations in respect of R⁵ and R⁶ mayalso be present in the moieties of the compounds of the presentinvention in which only two of R⁴, R⁵, R⁶, R⁷ and R⁸ are H.

When two of R⁴ to R⁸ are a group other than hydrogen in the moieties ofthe compounds of the present invention, group B as defined in formula(I) is preferably selected from the group consisting of

where * is as previously defined. When group B as defined in formula (I)is selected from this group and one of R¹ or R² is a phenyl groupsubstituted with at least one substituent represented by the group R³,in some embodiments R³ may be selected from the group consisting of H,Cl, F, Br, —CF₃, —OCF₃, and ethynyl. In these embodiments, the other ofR¹ or R² (i.e. that which is not a phenyl group substituted with atleast one substituent represented by the group R³) is —CH₂N(CH₃)₂ orchlorine, preferably hydrogen, more preferably —CH₃. In some suchembodiments, at least one of the substituents represented by R³ isselected from the group consisting of para-Br, para-CF₃, para-OCF₃ andpara-ethynyl, and in some of these embodiments R³ represents a singlesubstituent selected from the group consisting of para-Br, para-CF₃,para-OCF₃ and para-ethynyl.

In the moieties of the compounds of the present invention, more than oneof R⁴ to R⁸ may be a group other than hydrogen. In some embodiments ofthe present invention only one of R⁴ to R⁸ is a group other thanhydrogen. In some embodiments only R⁴ is a group other than hydrogen. Insome embodiments only R⁵ is a group other than hydrogen. In someembodiments only R⁶ is a group other than hydrogen. In some embodimentsonly R⁷ is a group other than hydrogen. In some embodiments only R⁸ is agroup other than hydrogen.

When only one of R⁴ to R⁸ is a group other than hydrogen in the moietiesof the compounds of the present invention, group B as defined in formula(I) is preferably selected from the group consisting of

In some embodiments of the present invention, three of R⁴ to R⁸ may be agroup other than hydrogen. When three of R⁴ to R⁸ is a group other thanhydrogen in the moieties of the compounds of the present invention,group B as defined in formula (I) is preferably

where * is as defined above.

In the moieties of the compounds of the present invention, R³ representsoptional substituents on an otherwise unsubstituted phenyl ring and ispreferably independently selected from the group consisting of one ormore substituents selected from the group consisting of —CH₃,C_(2to4)alkyl, halogen, hydroxyl, —OCH₃, —OC_(2to4)alkyl, ethynyl,—OCF₃, and —CF₃, more preferably one or more substituents independentlyselected from the group consisting of —CH₃, —CH₂CH₃, —OH, —CF₃, —OCF₃,ethynyl, and halogen, wherein halogen is preferably F or Cl or Br, mostpreferably independently selected from one or more substituents selectedthe group consisting of —CH₃, —CH₂CH₃, —CF₃, —OCF₃, ethynyl, andhalogen, wherein halogen is preferably F or Cl or Br. In someembodiments, R³ can be one substituent, two substituents or threesubstituents independently selected from either of these lists. R³ ispreferably two substituents independently selected from either theselists, more preferably one substituent selected from either of theselists.

R³ may represent an ortho-, meta- or para-substituent. In someembodiments of the invention, one of the at least one substituentsrepresented by R³ is selected from the group consisting of para-Br,para-F, para-Cl, para-ethyl, para-CF₃, para-OCF₃ and para-ethynyl. Insome embodiments of the invention, R³ represents a single substituent onthe phenyl ring and is selected from the group consisting of para-Br,para-F, para-Cl, para-ethyl, para-CF₃, para-OCF₃ and para-ethynyl. Insome embodiments of the invention, one of the at least one substituentsrepresented by R³ is meta-Cl. In some embodiments of the invention, oneof the at least one substituents represented by R³ is ortho-Cl. In someembodiments of the invention, one of the at least one substituentsrepresented by R³ is ortho-methyl. In some embodiments of the invention,R³ represents at least two substituents. In some embodiments of theinvention in which R³ represents at least two substituents, two of thesubstituents represented by R³ are ortho-Cl and para-Cl.

When R³ represents two substituents, they may be ortho, meta or para toone another. In such embodiments, the phenyl ring which is substitutedwith the two R³ substituents may be a 2,3-disubstituted phenyl ring, a2,4-disubstituted phenyl ring, a 2,5-disubstituted phenyl ring, a2,6-disubstituted phenyl ring, a 3,4-disubstituted phenyl ring or a3,5-disubstituted phenyl ring.

When R¹ or R² is an optionally substituted phenyl ring in the presentinvention, they are preferably selected from

In a further embodiment of the present invention, the moieties offormula (I) are represented by the formulae of List 7, where R³represents optional substituents on an otherwise unsubstituted phenylring and is preferably selected from the group consisting of one or moresubstituents selected from the group consisting of —CH₃, C_(2to4)alkyl,halogen, hydroxyl, —OCH₃, —OC_(2to4)alkyl, ethynyl, —OCF₃, and —CF₃,more preferably one or more substituents independently selected from thegroup consisting of —CH₃, —CH₂CH₃, —OH, —CF₃, —OCF₃, ethynyl, andhalogen, wherein halogen is preferably F or Cl or Br, most preferablyindependently selected from one or more substituents selected the groupconsisting of —CH₃, —CH₂CH₃, —CF₃, —OCF₃, ethynyl, and halogen, whereinhalogen is preferably F or Cl or Br, and the furan ring may beoptionally further substituted, preferably by one or more substituents,independently selected from —CH₃, C_(2to4)alkyl, halogen, —OCH₃, and—OC_(2to4)alkyl, more preferably by one or more substituentsindependently selected from —CH₃, C_(2to4)alkyl and halogen, mostpreferably by one or more —CH₃ substituents.

In some embodiments, in the moieties of formula (I) represented bycompounds (XV), (XVI), (XVII) and (XVIII) in List 7 R³ is H. In someembodiments, in the moieties of formula (I) represented by compounds(XV), (XVI), (XVII) and (XVIII) in List 7 R³ is halogen, preferably F orCl or Br. In other embodiments, in the moieties of formula (I)represented by compounds (XV), (XVI), (XVII) and (XVIII) in List 7 R³ is—CF₃, —OCF₃, —CH₃, ethyl, or —C≡CH. It has been found that examples ofsuch compounds which show excellent activity in the assays of theinvention include formula (XV) in which R³ is para-Cl, formula (XV) inwhich R³ is meta-Cl, formula (XV) in which R³ is para-CH₃, formula (XVI)in which R³ is para-Cl, formula (XV) in which R³ is meta-Cl, formula(XVII) in which R³ is para-Cl, formula (XV) in which R³ is para-OCF₃,formula (XV) in which R³ is para-CF₃, formula (XV) in which R³ ispara-C≡CH, formula (XV) in which R³ is ortho-CH₃, formula (XVIII) inwhich R³ is para-OCF₃, formula (XVIII) in which R³ is para-CF₃.

In a further embodiment of the present invention, the moieties offormula (I) are represented by the formulae of List 8, where R⁴, R⁵, R⁷and R⁸ are independently selected from the group consisting of H, —CH₃,C_(2to4)alkyl, halogen, hydroxyl, —OCH₃, —OC_(2to4)alkyl, —CF₃, —OCF₃,—NH₂, —CH₂NH₂, —N(CH₃)₂, —NO₂, —CH₂OH, —CO₂CH₃, —CO₂C_(2to4)alkyl,—CO₂H, —N(alkyl)₂ where the two alkyl groups are independently selectedfrom —CH₃ or C_(2to4)alkyl, —NH(alkyl) where the alkyl group is selectedfrom —CH₃ or C_(2to4)alkyl, 4-morpholinyl, 1-piperidinyl,4H-piperazinyl, 4-C_(1to4)alkyl-piperazinyl, and4-C_(3to6)cycloalkyl-piperazinyl, preferably independently selected fromthe group consisting of H, —CH₃, C_(2to4)alkyl, iso-propyl, tert-butyl,halogen wherein halogen is preferably F or Cl or Br, hydroxyl, —OCH₃,—CF₃, —OCF₃, —N(CH₃)₂, —NO₂, and 4-methylpiperazinyl, more preferablyindependently selected from the group consisting of H, —CH₃, —CH₂CH₃,iso-propyl, —N(CH₃)₂, halogen wherein halogen is preferably F or Cl orBr, —OCH₃, —CF₃, and —OCF₃, and the furan ring may be optionally furthersubstituted, preferably by one or more substituents independentlyselected from —CH₃, C_(2to4)alkyl, halogen, —OCH₃, and —OC_(2to4)alkyl,preferably by one or more substituents independently selected from —CH₃,C_(2to4)alkyl, and halogen, most preferably by one or more —CH₃substituents.

In some embodiments, in the formulae of List 8 one of R⁴, R⁵, R⁷ or R⁸is —CF₃ or —OCF₃. In one aspect of the embodiment, one of R⁴, R⁵, R⁷ orR⁸ is —CF₃. In another aspect of the embodiment, one of R⁴, R⁵, R⁷ or R⁸is —OCF₃. The two groups labeled “halogen” in formula (XIX), i.e. thegroups corresponding respectively to an R⁶ substituent and an R³substituent, are preferably independently selected from the groupconsisting of F, Cl, and Br. In some embodiments, the group labeled“halogen” in formula (XIX) which corresponds to an R⁶ substituent is Cl.In some embodiments, the group labeled “halogen” in formula (XIX) whichcorresponds to an R⁶ substituent is F. In some embodiments, the grouplabeled “halogen” in formula (XIX) which corresponds to an R⁶substituent is Br. In some embodiments, the group labeled “halogen” informula (XIX) which corresponds to an R³ substituent is Br. In someembodiments, the group labeled “halogen” in formula (XIX) whichcorresponds to an R³ substituent is Cl. In some embodiments, the grouplabeled “halogen” in formula (XIX) which corresponds to an R³substituent is F. In some embodiments, the group labeled “halogen” informula (XIX) which corresponds to an R⁶ substituent is Cl and the grouplabeled “halogen” in formula (XIX) which corresponds to an R³substituent is Cl. In some embodiments, the group labeled “halogen” informula (XIX) which corresponds to an R⁶ substituent is Cl and the grouplabeled “halogen” in formula (XIX) which corresponds to an R³substituent is Br. In some embodiments, the group labeled “halogen” informula (XIX) which corresponds to an R⁶ substituent is Cl and the grouplabeled “halogen” in formula (XIX) which corresponds to an R³substituent is F. In some embodiments, the group labeled “halogen” informula (XIX) which corresponds to an R⁶ substituent is F and the grouplabeled “halogen” in formula (XIX) which corresponds to an R³substituent is Cl. In some embodiments, the group labeled “halogen” informula (XIX) which corresponds to an R⁶ substituent is F and the grouplabeled “halogen” in formula (XIX) which corresponds to an R³substituent is Br. In some embodiments, the group labeled “halogen” informula (XIX) which corresponds to an R⁶ substituent is F and the grouplabeled “halogen” in formula (XIX) which corresponds to an R³substituent is F. In some embodiments, the group labeled “halogen” informula (XIX) which corresponds to an R⁶ substituent is Br and the grouplabeled “halogen” in formula (XIX) which corresponds to an R³substituent is Cl. In some embodiments, the group labeled “halogen” informula (XIX) which corresponds to an R⁶ substituent is Br and the grouplabeled “halogen” in formula (XIX) which corresponds to an R³substituent is Br. In some embodiments, the group labeled “halogen” informula (XIX) which corresponds to an R⁶ substituent is Br and the grouplabeled “halogen” in formula (XIX) which corresponds to an R³substituent is F.

The compounds described in lists 7 and 8 may find particular use in thetreatment of microbial infections caused by a wide spectrum ofgram-positive bacteria including Enterococci, for example Enterococcusfaecium or Enterococcus faecalis.

In some embodiments of the invention, the moiety of formula (I) isrepresented by the formula (XIXa) shown in List 9.

In the moiety of List 9, group A and group B are as defined for formula(I) and R² is an alkyl group selected from the group consisting ofC_(3to6)alkyl and C_(3to6)cycloalkyl, and is preferably selected fromthe group consisting of n-propyl, n-butyl, and iso-butyl. In someembodiments R² is n-propyl. In some embodiments R² is n-butyl. In someembodiments R² is iso-butyl.

In some embodiments of the invention in which R¹ is aryl, heteroaryl, orbenzyl or benzyl substituted on the phenyl ring, and Y is C, R² is H.

In some embodiments of the invention in which R¹ is aryl, heteroaryl, orbenzyl or benzyl substituted on the phenyl ring, and Y is C, R² is —CH₃.

In some embodiments of the invention in which R¹ is aryl, heteroaryl, orbenzyl or benzyl substituted on the phenyl ring, and Y is C, R² is—CH₂N(CH₃)₂.

In some embodiments of the invention in which R¹ is aryl, heteroaryl, orbenzyl or benzyl substituted on the phenyl ring, and Y is C, R² ishalogen, in particular chlorine.

In some embodiments of the invention in which R² is aryl, heteroaryl, orbenzyl or benzyl substituted on the phenyl ring, and Y is C, R¹ is H.

In some embodiments of the invention in which R² is aryl, heteroaryl, orbenzyl or benzyl substituted on the phenyl ring, and Y is C, R¹ is —CH₃.

In some embodiments of the invention in which R² is aryl, heteroaryl, orbenzyl or benzyl substituted on the phenyl ring, and Y is C, R¹ is—CH₂N(CH₃)₂.

In some embodiments of the invention in which R² is aryl, heteroaryl, orbenzyl or benzyl substituted on the phenyl ring, and Y is C, R¹ ishalogen, in particular chlorine.

In some embodiments of the invention, the group representing B in themoiety of formula (I) is a 2-chloro-4-trifluoromethylphenyl group. Insome embodiments of the invention, the group representing B in themoiety of formula (I) is a 2-chloro-4-trifluoromethoxyphenyl group.

In some embodiments of the invention, the group representing B in themoiety of formula (I) is a 3-chloro-4-trifluoromethylphenyl group. Insome embodiments of the invention, the group representing B in themoiety of formula (I) is a 3-chloro-4-trifluoromethoxyphenyl group.

In some embodiments of the invention, the group representing B in themoiety of formula (I) is a 4-chloro-3-trifluoromethylphenyl group. Insome embodiments of the invention, the group representing B in themoiety of formula (I) is a 4-chloro-3-trifluoromethoxyphenyl group.

In some preferred embodiments of the invention, when the grouprepresenting A is a furan joined at the 2-position of the furan ring tothe group representing B and joined at the 5-position of the furan ringto the 5-membered heterocyclic ring which is substituted with R¹ and R²(i.e. A is furan-2,5-diyl), the furan ring carries no furthersubstituents, i.e. the furan moiety representing A comprises twounsubstituted positions on the furan ring.

In any of the formulae (IV) to (VIII) or in any of the formulae of lists1 to 8, the moiety representing

of formula (I), where *** is the point of connection to A, may bereplaced with the moiety

with R¹ being as defined for formula (I).

In a preferred embodiment, the compounds of the invention comprise atleast one F atom. In some embodiments, the compounds of the inventioncomprise at least three F atoms. Further, the compounds of the inventionmay comprise at least one or more F atoms and/or Cl atoms. In someembodiments, the compounds of the invention comprise at least two Clatoms. In some embodiments, the compounds of the invention comprise atleast two O atoms. In some embodiments, the compounds of the inventioncomprise at least three N atoms. In some embodiments, the compounds ofthe invention comprise at least one —CH₃ group. In some embodiments, thecompounds of the invention comprise at least one —CF₃ or —OCF₃ group. Insome embodiments, the compounds of the invention comprise at least one—CF₃ or —OCF₃ group and at least one halogen atom. In some embodiments,the compounds of the invention comprise at least one —CF₃ or —OCF₃ groupand at least one Cl atom. In some embodiments, the compounds of theinvention comprise at least one —CF₃ or —OCF₃ group and at least one Fatom. In some embodiments, the compounds of the invention comprise atleast one —CF₃ or —OCF₃ group and at least one Br atom. In someembodiments, the compounds of the invention comprise at least one —CF₃or —OCF₃ group and at least one —CH₃ group.

In some embodiments of the present invention, the number of carbon atomsin the group representing R¹ differs from the number of carbon atoms inthe group representing R² by one carbon atom. In some embodiments of thepresent invention, the number of carbon atoms in the group representingR¹ differs from the number of carbon atoms in the group representing R²by two carbon atoms. In some embodiments of the present invention, thenumber of carbon atoms in the group representing R¹ differs from thenumber of carbon atoms in the group representing R² by three carbonatoms. In some embodiments of the present invention, the number ofcarbon atoms in the group representing R¹ differs from the number ofcarbon atoms in the group representing R² by four carbon atoms. In someembodiments of the present invention, the number of carbon atoms in thegroup representing R¹ differs from the number of carbon atoms in thegroup representing R² by five carbon atoms. In some embodiments of thepresent invention, the number of carbon atoms in the group representingR¹ differs from the number of carbon atoms in the group representing R²by six carbon atoms. In some embodiments of the present invention, thenumber of carbon atoms in the group representing R¹ differs from thenumber of carbon atoms in the group representing R² by seven carbonatoms. In some embodiments of the present invention, the number ofcarbon atoms in the group representing R¹ differs from the number ofcarbon atoms in the group representing R² by eight carbon atoms. In someembodiments of the present invention, the number of carbon atoms in thegroup representing R¹ differs from the number of carbon atoms in thegroup representing R² by nine carbon atoms. In some embodiments of thepresent invention, the number of carbon atoms in the group representingR¹ differs from the number of carbon atoms in the group representing R²by ten carbon atoms. In some embodiments of the present invention, thenumber of carbon atoms in the group representing R¹ differs from thenumber of carbon atoms in the group representing R² by eleven carbonatoms. In some embodiments of the present invention, the number ofcarbon atoms in the group representing R¹ differs from the number ofcarbon atoms in the group representing R² by twelve carbon atoms.

In the compounds of the present invention, R¹ and R² can be connected toform a four-, five- or six-membered non-aromatic carbocyclic ring thusproviding a fused bicyclic moiety in which one or more of the carbonatoms of the ring comprising groups R¹ and R² is optionally replaced bya heteroatom selected from O, N, or S. Accordingly, fully aromaticbicycles, i.e. bicycles in which both rings are aromatic, do not fallunder the present invention. For example, R¹ and R² cannot be connectedto form a phenyl ring, thus giving rise to a benzimidazole.

The bond linking the ring bearing the substituents R¹ and R² of thecompounds of the present invention to the rings represented by A ispreferably a carbon-carbon (C—C) single bond.

In the present invention, A is aryl or heteroaryl. A is therefore anaromatic ring. “Aromatic” in the context of the present invention meansthat, at ambient (room) temperature (20° C.), the corresponding ringexists in the aromatic form (in the case of tautomers, in the aromatictautomeric form) preferably to the degree of at least 10, 20, 30, 40,50, 60, 70, 80, or 90%. Preferably, “aromatic” means that thecorresponding ring exists at room temperature in the aromatic form tothe degree of at least 95%, more preferably at least 99%, still morepreferably at least 99.5% or at least 99.9%.

When the A ring is substituted in the compounds of the presentinvention, it is preferably not substituted with an acyl substituent,i.e. it is preferred that no atom of the A ring is directly bonded to acarbonyl group.

In the compounds of the present invention, the bond linking the groupscorresponding to A and B in formula (I) is preferably a single covalentbond and may be, for example, a C—C single bond, a C—N single bond, or aN—C single bond.

It is preferred that R¹ and R² are not both aryl or both phenyl, e.g. ifR¹ is phenyl, R² is preferably not phenyl or aryl. Preferably, if R¹ isunsubstituted phenyl, R² is not unsubstituted phenyl. Preferably, if R¹is substituted phenyl, R² is not substituted phenyl. Preferably, if R¹is substituted phenyl, R² is not unsubstituted phenyl. Preferably, if R¹is unsubstituted phenyl, R² is not substituted phenyl. Preferably, if R¹is substituted aryl, R² is not substituted aryl. Preferably, if R¹ isunsubstituted aryl, R² is not unsubstituted aryl. Preferably, if R¹ issubstituted aryl, R² is not unsubstituted aryl. Preferably, if R¹ isunsubstituted aryl, R² is not substituted aryl.

R¹ and R² are preferably not both heteroaryl, i.e. if R¹ is heteroaryl,R² is preferably not heteroaryl. Preferably, if R¹ is unsubstitutedheteroaryl, R² is not unsubstituted heteroaryl. Preferably, if R¹ issubstituted heteroaryl, R² is not substituted heteroaryl. Preferably, ifR¹ is substituted heteroaryl, R² is not unsubstituted heteroaryl.Preferably, if R¹ is unsubstituted heteroaryl, R² is not substitutedheteroaryl.

R¹ and R² are preferably not both aromatic rings, e.g. if R¹ is aryl, R²is preferably not heteroaryl. Preferably, if R¹ is substituted orunsubstituted heteroaryl, R² is not substituted or unsubstituted aryl orphenyl. Preferably, if R¹ is substituted heteroaryl, R² is notsubstituted or unsubstituted aryl or phenyl. Preferably, if R¹ isunsubstituted heteroaryl, R² is not substituted or unsubstituted aryl orphenyl.

R¹ and R² are preferably not both benzyl optionally substituted on thephenyl ring, i.e. if R¹ is benzyl optionally substituted on the phenylring, R² is preferably not benzyl optionally substituted on the phenylring. Preferably, if R¹ is benzyl unsubstituted on the phenyl ring, R²is not benzyl unsubstituted on the phenyl ring. Preferably, if R¹ isbenzyl substituted on the phenyl ring, R² is not benzyl substituted onthe phenyl ring. Preferably, if R¹ is benzyl substituted on the phenylring, R² is not benzyl unsubstituted on the phenyl ring. Preferably, ifR¹ is benzyl unsubstituted on the phenyl ring, R² is not benzylsubstituted on the phenyl ring.

If one of R¹ or R² is benzyl optionally substituted on the phenyl ring,the other of R¹ or R² is preferably not substituted or unsubstitutedphenyl. If one of R¹ or R² is benzyl optionally substituted on thephenyl ring, the other of R¹ or R² is preferably not substituted orunsubstituted aryl. If one of R¹ or R² is benzyl optionally substitutedon the phenyl ring, the other of R¹ or R² is preferably not substitutedor unsubstituted heteroaryl. If one of R¹ or R² is benzyl optionallysubstituted on the phenyl ring, the other of R¹ or R² is preferably nota substituted or unsubstituted aromatic group.

In the compounds of the present invention, if one of R¹ or R² is H, theother of R¹ or R² is preferably not CH₃, or C_(2to6)alkyl.

The imidazole/triazole ring (i.e. the ring substituted with R¹ and R²)and the B ring of the compounds of the present invention preferably donot constitute substituents on the A ring of the compounds of thepresent invention exhibiting a relative 1,2-substitution pattern, i.e.they are preferably not respectively bonded to atoms of the A ring(irrespective of IUPAC numbering of the atoms of the given ring) whichare directly adjacent to one another. Preferably the B ring and theimidazole ring constitute substituents exhibiting a relative 1,3-,preferably a relative 1,4-substitution pattern, e.g. in the case of Abeing a furan ring these substituents are present at the 4- and 2-, or2- and 4-positions respectively, preferably at the 2- and 5-, or 5- and2-positions of the furan ring.

When in the compounds of the present invention the A ring isunsubstituted or substituted pyrrazole, the A ring preferably does notconstitute a pyrrazole ring with a free NH group, i.e. it is preferredthat the valency of all N atoms in the pyrrazole ring is completelysatisfied through bonding to non-hydrogen atoms.

When in the compounds of the present invention the A ring isunsubstituted or substituted pyrrazole, the A ring is preferably notdirectly joined to the group representing the B ring of the compounds ofthe present invention via a C-atom of the pyrrazole ring.

When in the compounds of the present invention the A ring isunsubstituted or substituted pyrrazole, the imidazole/triazole ring(i.e. the ring substituted with R¹ and R²) and the group representingthe B ring of the compounds of the present invention are preferably notjoined to the pyrrazole at its 3- and 5-positions or 5- and 3-positions.

When in the compounds of the present invention the A ring isunsubstituted or substituted pyrrazole, the A ring is preferably notsubstituted with a hydroxyl group.

In the compounds of the present invention, the B ring is preferably notan unsubstituted 2-thiophene ring, more preferably not a 2-thiophenering, still more preferably not an unsubstituted thiophene ring, stillmore preferred not a thiophene ring.

In the compounds of the present invention, the B ring is preferably nota 5-membered S-containing heteroaryl ring. In the compounds of thepresent invention, the group representing the B ring is preferably not a5-membered heteroaryl ring containing only one heteroatom.

In the compounds of the present invention, the B ring is preferably nota 1-indolyl group, more preferably not a substituted 1-indolyl group.

In the compounds of the present invention, the B ring is preferably nota 1-indolyl group when the group representing the A ring is a2,4-disubstituted thiazole. In the compounds of the present invention,the B ring is preferably not a 1-indolyl group when the grouprepresenting the A ring contains two heteroatoms.

In the compounds of the present invention, when one of R¹ or R² is H thegroup representing the B ring is preferably not a 1-indolyl group.

In the compounds of the present invention, when the A ring is a pyrrolering it is preferably not directly substituted with both an O-atom and aN-atom. In the compounds of the present invention, when the A ring is apyrrole ring it is preferably substituted with no more than oneadditional substituent. In the compounds of the present invention, whenthe A ring is a pyrrole ring it is preferably not a hydroxyl-substitutedpyrrole ring. In the compounds of the present invention, when the A ringis a pyrrole ring it is preferably not a NH₂-substituted pyrrole ring.

In the compounds of the present invention, the A ring is preferably notsubstituted with an aromatic ring which is other than an aromatic ringbelonging to B or the aromatic ring bearing the substituents R¹ and R².

In the compounds of the present invention, the A ring is preferably nota tetrasubstituted pyrrazole, more preferably not a tetrasubstitutedring.

When in the compounds of the present invention the A ring is anunsubstituted or substituted pyrrazole, the imidazole/triazole ring(i.e. the ring substituted with R¹ and R²) and the B ring of thecompounds of the present invention are preferably not respectivelyjoined to the pyrrazole at its 1- and 3-positions or 3- and 1-positions.

In the compounds of the present invention, the A ring is preferably notan oxazole ring exhibiting substituents at both the 4- and 5-positions.

In the compounds of the present invention, when R¹ or R² is aryl, theyare preferably selected from the group consisting of phenyl, naphthyl,anthracyl, and penanthracyl, where each of these groups can besubstituted or unsubstituted. When R¹ or R² is aryl they are preferablysubstituted or unsubstituted phenyl.

When R¹ or R² is heteroaryl, they are preferably selected from the groupconsisting of 5-membered single ring heteroaryl, 6-membered single ringheteroaryl, and bicyclic fused ring heteroaryl.

In the compounds of the present invention, when the A ring is aryl it ispreferably selected from the group consisting of phenyl, naphthyl,anthracyl, and penanthracyl, where each of these groups can besubstituted or unsubstituted. When A is aryl it is preferablysubstituted or unsubstituted phenyl or naphthyl.

In the compounds of the present invention, when the A ring isheteroaryl, it is preferably selected from the group consisting of5-membered (single ring) heteroaryl, 6-membered (single ringheteroaryl), and bicyclic fused ring heteroaryl. In the compounds of thepresent invention, when the A ring is heteroaryl, it is preferably5-membered (single ring) heteroaryl.

In the compounds of the present invention, when the B ring is aryl, itis preferably selected from the group consisting of phenyl, naphthyl,anthracyl, and penanthracyl, where each of these groups can besubstituted or unsubstituted. When B is aryl, it is preferablysubstituted or unsubstituted phenyl or naphthyl.

In the compounds of the present invention, when the B ring isheteroaryl, it is preferably selected from the group consisting of5-membered (single ring) heteroaryl, 6-membered (single ring)heteroaryl, and bicyclic fused ring heteroaryl.

When B is bicyclic fused ring heteroaryl, it is preferably selected fromthe group consisting of indolyl (e.g. 1-, 2-, 3-, 4-, 5-, 6-, or7-indolyl), benzofuranyl (e.g. 2-, 3-, 4-, 5-, 6-, or 7-benzofuranyl),indazolyl (e.g. 1-, 3-, 4-, 5-, 6-, or 7-indazolyl), oxindolyl (e.g. 1-,3-, 4-, 5-, 6-, or 7-oxindolyl), benzimidazolyl (e.g. 1-, 2-, 4-, 5-,6-, or 7-benzimidazolyl), benzothiophenyl (e.g. 2-, 3-, 4-, 5-, 6-, or7-benzothiophenyl), benzoxazolyl (e.g. 2-, 4-, 5-, 6-, or7-benzoxazolyl), benzo[d]thiazolyl (e.g. 2-, 4-, 5-, 6-, or7-benzo[d]thiazolyl), quinolinyl (e.g. 2-, 3-, 4-, 5-, 6-, 7-, or8-quinolinyl), isoquinolinyl (e.g. 1-, 3-, 4-, 5-, 6-, 7-, or8-isoquinolinyl), coumarinyl (e.g. 3-, 4-, 5-, 6-, 7-, or 8-coumarinyl),purinyl (e.g. 2-, 6-, 8-, or 9-purinyl), 1,2-diazanaphthyl (e.g. 3-, 4-,5-, 6-, 7-, 8-(1,2-diazanaphth)-yl), 1,3-diazanaphthyl (e.g. 2-, 4-, 5-,6-, 7-, 8-(1,3-diazanaphth)-yl), 1,4-diazanaphthyl (e.g. 2-, 3-, 5-, 6-,7-, 8-(1,4-diazanaphth)-yl), 1,5-diazanaphthyl (e.g. 2-, 3-, 4-, 6-, 7-,8-(1,5-diazanaphth)-yl), 1,6-diazanaphthyl (e.g. 2-, 3-, 4-, 5-, 7-,8-(1,6-diazanaphth)-yl), 1,7-diazanaphthyl (e.g. 2-, 3-, 4-, 5-, 6-,8-(1,7-diazanaphth)-yl), 1,8-diazanaphthyl (e.g. 2-, 3-, 4-, 5-, 6-,7-(1,8-diazanaphth)-yl), 2,3-diazanaphthyl (e.g. 1-, 4-, 5-, 6-, 7-,8-(2,3-diazanaphth)-yl), 2,6-diazanaphthyl (e.g. 1-, 3-, 4-, 5-, 7-,8-(2,6-diazanaphth)-yl), and 2,7-diazanaphthyl (e.g. 1-, 3-, 4-, 5-, 6-,8-(2,7-diazanaphth)-yl). More preferably when B is bicyclic fused ringheteroaryl, it is selected from the group consisting of indolyl (e.g.1-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl), benzofuranyl (e.g. 2-, 3-, 4-,5-, 6-, or 7-benzofuranyl), indazolyl (e.g. 1-, 3-, 4-, 5-, 6-, or7-indazolyl), and oxindolyl (e.g. 1-, 3-, 4-, 5-, 6-, or 7-oxindolyl).

In an exemplary aspect of the invention, when the groups describedherein are said to be “substituted or unsubstituted”, “optionallysubstituted”, or “substituted”, when substituted, they may be preferablysubstituted with one or more of any substituent. Examples of suchsubstituents are those found in the exemplary compounds and embodimentsdisclosed herein, as well as, for example, halo (e.g., chloro, iodo,bromo, or fluoro); C_(1- or 2-8) alkyl; C_(1- or 2-8) alkyl substitutedwith one or more substituents independently selected from OH, NH₂,NHCH₃, N(CH₃)₂, NH(C₂₋₆alkyl), N(C₂₋₆alkyl)₂, SH, SCH₃, SC₂₋₆alkyl, CN,CONH₂, CO₂H, NO₂, SO₂H, SO₂CH₃, and SO₂Aryl; C₂₋₈ alkenyl; C₂₋₈ alkynyl;hydroxyl; C_(1- or 2-8) alkoxyl; —NH₂; —NHCH₃; —NHC₂₋₆ alkyl; —N(CH₃)₂;—N(C₂₋₆ alkyl)₂; amino (primary, secondary, or tertiary); —NO₂; —SH;—SCH₃; —SC₂₋₆ alkyl; —C═NH; —C═NCH₃; —C═NC₂₋₆alkyl; —CN; —CONH₂;—CONHCH₃; —CONHC₂₋₆alkyl; —CON(CH₃)₂; —CON(C₂₋₆ alkyl)₂; phosphonato;—P(O)(OH)₂; —P(O)(OH)(OCH₃); —P(O)(OCH₃)₂; —P(O)(OH)(OC₂₋₆ alkyl);—P(O)(OC₂₋₆ alkyl)₂; —OP(O)(OH)₂; —OP(O)(OH)(OCH₃); —OP(O)(OCH₃)₂;—OP(O)(OH)(OC₂₋₆ alkyl); —OP(O)(OC₂₋₆ alkyl)₂; phosphine; —P(CH₃)₂;—P(C₂₋₆ alkyl)₂; —P(C₃₋₆ cycloalkyl)₂; —P(Aryl)₂; —P(Phenyl)₂;—P(Heteroaryl)₂; carboxyl; —CO₂H; carbamoyl; —OCONH₂; —OCONHCH₃;—OCON(CH₃)C₂₋₆ alkyl; —OCON(CH₃)C₃₋₆ cycloalkyl; —OCON(CH₃)Aryl;—OCON(CH₃)Phenyl; —OCON(CH₃)Heteroaryl; —OCON(CH₃)₂; —OCONHC₂₋₆ alkyl;—OCON(C₂₋₆ alkyl)C₃₋₆ cycloalkyl; —OCON(C₂₋₆ alkyl)Aryl; —OCON(C₂₋₆alkyl)Phenyl; —OCON(C₂₋₆ alkyl)Heteroaryl; —OCON(C₂₋₆ alkyl)₂;—OCONHC₃₋₆ cycloalkyl; —OCON(C₃₋₆ cycloalkyl)Aryl; —OCON(C₃₋₆cycloalkyl)Phenyl; —OCON(C₃₋₆ cycloalkyl)Heteroaryl; —OCON(C₃₋₆cycloalkyl)₂; —OCONHAryl; —OCON(Aryl)Phenyl; —OCON(Aryl)Heteroaryl;—OCON(Aryl)₂; —OCONHPhenyl; —OCON(Phenyl)Heteroaryl; —OCON(Phenyl)₂;—OCONHHeteroaryl; —OCON(Heteroaryl)₂; —OCON(CH₃)₂; —OCON(C₂₋₆ alkyl)₂;—OCONCH₃(C₂₋₆ alkyl); —NHCOOCH₃; —NHCOOC₂₋₆ alkyl; —NHCOOC₃₋₆cycloalkyl;—NHCOOAryl; —NHCOOPhenyl; —NHCOO(Heteroaryl); —N(CH₃)COOCH₃;—N(CH₃)COOC₂₋₆ alkyl; —N(CH₃)COOC₃₋₆cycloalkyl; —N(CH₃)COOAryl;—N(CH₃)COOPhenyl; —N(CH₃)COO(Heteroaryl); —N(C₂₋₆ alkyl)COOCH₃; —N(C₂₋₆alkyl)COOC₂₋₆ alkyl; —N(C₂₋₆ alkyl)COOC₃₋₆cycloalkyl; —N(C₂₋₆alkyl)COOAryl; —N(C₂₋₆ alkyl)COOPhenyl; —N(C₂₋₆ alkyl)COO(Heteroaryl);—N(COOC₃₋₆cycloalkyl)COOCH₃; —N(COOC₃₋₆cycloalkyl)COOC₂₋₆ alkyl;—N(COOC₃₋₆cycloalkyl)COOC₃₋₆cycloalkyl; —N(COOC₃₋₆cycloalkyl)COOAryl;—N(COOC₃₋₆cycloalkyl)COOPhenyl; —N(COOC₃₋₆cycloalkyl)COO(Heteroaryl);—N(Aryl)COOCH₃; —N(Aryl)COOC₂₋₆ alkyl; —N(Aryl)COOC₃₋₆cycloalkyl;—N(Aryl)COOAryl; —N(Aryl)COOPhenyl; —N(Aryl)COO(Heteroaryl);—N(Phenyl)COOCH₃; —N(Phenyl)COOC₂₋₆ alkyl; —N(Phenyl)COOC₃₋₆cycloalkyl;—N(Phenyl)COOAryl; —N(Phenyl)COOPhenyl; —N(Phenyl)COO(Heteroaryl);—N(Heteroaryl)COOCH₃; —N(Heteroaryl)COOC₂₋₆ alkyl;—N(Heteroaryl)COOC₃₋₆cycloalkyl; —N(Heteroaryl)COOAryl;—N(Heteroaryl)COOPhenyl; —N(Heteroaryl)COO(Heteroaryl); —NCOOCH₃;—N(CH₃)COOC₂₋₆ alkyl; —N(C₂₋₆ alkyl)COOCH₃; —N(C₂₋₆ alkyl)COOC₂₋₆ alkyl;carbamate; acetal; urea; —NHCONH₂; —NHCONH(CH₃); NHCON(CH₃)₂;—NHCONH(C₂₋₆ alkyl); —NHCON(C₂₋₆ alkyl)₂; —NHCONHC₃₋₆ cycloalkyl;—NHCON(C₃₋₆ cycloalkyl)₂; —NHCONHAryl; —NHCON(Aryl)₂; —NHCONHPhenyl;—NHCON(Phenyl)₂; —NHCONHHeteroaryl; —NHCON(Heteroaryl)₂;—NHCON(CH₃)(C₂₋₆ alkyl); —NHCON(CH₃)(C₃₋₆ cycloalkyl);—NHCON(CH₃)(Aryl); —NHCON(CH₃)(Phenyl); —NHCON(CH₃)(Heteroaryl);—NHCON(C₂₋₆ alkyl)(C₃₋₆ cycloalkyl); —NHCON(C₂₋₆ alkyl)(Aryl);—NHCON(C₂₋₆ alkyl)(Phenyl); —NHCON(C₂₋₆ alkyl)(Heteroaryl); —NHCON(C₃₋₆cycloalkyl)(Aryl); —NHCON(C₃₋₆ cycloalkyl)(Phenyl); —NHCON(C₃₋₆cycloalkyl)(Heteroaryl); —NHCON(Aryl)(Phenyl); —NHCON(Aryl)(Heteroaryl);—NHCON(Phenyl)(Heteroaryl); —N(CH₃)CONH₂; —N(CH₃)CONH(CH₃);N(CH₃)CON(CH₃)₂; —N(CH₃)CONH(C₂₋₆ alkyl); —N(CH₃)CON(C₂₋₆ alkyl)₂;—N(CH₃)CONHC₃₋₆ cycloalkyl; —N(CH₃)CON(C₃₋₆ cycloalkyl)₂;—N(CH₃)CONHAryl; —N(CH₃)CON(Aryl)₂; —N(CH₃)CONHPhenyl;—N(CH₃)CON(Phenyl)₂; —N(CH₃)CONHHeteroaryl; —N(CH₃)CON(Heteroaryl)₂;—N(CH₃)CON(CH₃)(C₂₋₆ alkyl); —N(CH₃)CON(CH₃)(C₃₋₆ cycloalkyl);—N(CH₃)CON(CH₃)(Aryl); —N(CH₃)CON(CH₃)(Phenyl);—N(CH₃)CON(CH₃)(Heteroaryl); —N(CH₃)CON(C₂₋₆ alkyl)(C₃₋₆ cycloalkyl);—N(CH₃)CON(C₂₋₆ alkyl)(Aryl); —N(CH₃)CON(C₂₋₆ alkyl)(Phenyl);—N(CH₃)CON(C₂₋₆ alkyl)(Heteroaryl); —N(CH₃)CON(C₃₋₆ cycloalkyl)(Aryl);—N(CH₃)CON(C₃₋₆ cycloalkyl)(Phenyl); —N(CH₃)CON(C₃₋₆cycloalkyl)(Heteroaryl); —N(CH₃)CON(Aryl)(Phenyl);—N(CH₃)CON(Aryl)(Heteroaryl); —N(CH₃)CON(Phenyl)(Heteroaryl); —N(C₂₋₆alkyl)CONH₂; —N(C₂₋₆ alkyl)CONH(CH₃); N(C₂₋₆ alkyl)CON(CH₃)₂; —N(C₂₋₆alkyl)CONH(C₂₋₆ alkyl); —N(C₂₋₆ alkyl)CON(C₂₋₆ alkyl)₂; —N(C₂₋₆alkyl)CONHC₃₋₆ cycloalkyl; —N(C₂₋₆ alkyl)CON(C₃₋₆ cycloalkyl)₂; —N(C₂₋₆alkyl)CONHAryl; —N(C₂₋₆ alkyl)CON(Aryl)₂; —N(C₂₋₆ alkyl)CONHPhenyl;—N(C₂₋₆ alkyl)CON(Phenyl)₂; —N(C₂₋₆ alkyl)CONHHeteroaryl; —N(C₂₋₆alkyl)CON(Heteroaryl)₂; —N(C₂₋₆ alkyl)CON(CH₃)(C₂₋₆ alkyl); —N(C₂₋₆alkyl)CON(CH₃)(C₃₋₆ cycloalkyl); —N(C₂₋₆ alkyl)CON(CH₃)(Aryl); —N(C₂₋₆alkyl)CON(CH₃)(Phenyl); —N(C₂₋₆ alkyl)CON(CH₃)(Heteroaryl); —N(C₂₋₆alkyl)CON(C₂₋₆ alkyl)(C₃₋₆ cycloalkyl); —N(C₂₋₆ alkyl)CON(C₂₋₆alkyl)(Aryl); —N(C₂₋₆ alkyl)CON(C₂₋₆ alkyl)(Phenyl); —N(C₂₋₆alkyl)CON(C₂₋₆ alkyl)(Heteroaryl); —N(C₂₋₆ alkyl)CON(C₃₋₆cycloalkyl)(Aryl); —N(C₂₋₆ alkyl)CON(C₃₋₆ cycloalkyl)(Phenyl); —N(C₂₋₆alkyl)CON(C₃₋₆ cycloalkyl)(Heteroaryl); —N(C₂₋₆ alkyl)CON(Aryl)(Phenyl);—N(C₂₋₆ alkyl)CON(Aryl)(Heteroaryl); —N(C₂₋₆alkyl)CON(Phenyl)(Heteroaryl); —N(C₃₋₆ cycloalkyl)CONH₂; —N(C₃₋₆cycloalkyl)CONH(CH₃); N(C₃₋₆ cycloalkyl)CON(CH₃)₂; —N(C₃₋₆cycloalkyl)CONH(C₂₋₆ alkyl); —N(C₃₋₆ cycloalkyl)CON(C₂₋₆ alkyl)₂;—N(C₃₋₆ cycloalkyl)CONHC₃₋₆ cycloalkyl; —N(C₃₋₆ cycloalkyl)CON(C₃₋₆cycloalkyl)₂; —N(C₃₋₆ cycloalkyl)CONHAryl; —N(C₃₋₆cycloalkyl)CON(Aryl)₂; —N(C₃₋₆ cycloalkyl)CONHPhenyl; —N(C₃₋₆cycloalkyl)CON(Phenyl)₂; —N(C₃₋₆ cycloalkyl)CONHHeteroaryl; —N(C₃₋₆cycloalkyl)CON(Heteroaryl)₂; —N(C₃₋₆ cycloalkyl)CON(CH₃)(C₂₋₆ alkyl);—N(C₃₋₆ cycloalkyl)CON(CH₃)(C₃₋₆ cycloalkyl); —N(C₃₋₆cycloalkyl)CON(CH₃)(Aryl); —N(C₃₋₆ cycloalkyl)CON(CH₃)(Phenyl); —N(C₃₋₆cycloalkyl)CON(CH₃)(Heteroaryl); —N(C₃₋₆ cycloalkyl)CON(C₂₋₆ alkyl)(C₃₋₆cycloalkyl); —N(C₃₋₆ cycloalkyl)CON(C₂₋₆ alkyl)(Aryl); —N(C₃₋₆cycloalkyl)CON(C₂₋₆ alkyl)(Phenyl); —N(C₃₋₆ cycloalkyl)CON(C₂₋₆alkyl)(Heteroaryl); —N(C₃₋₆ cycloalkyl)CON(C₃₋₆ cycloalkyl)(Aryl);—N(C₃₋₆ cycloalkyl)CON(C₃₋₆ cycloalkyl)(Phenyl); —N(C₃₋₆cycloalkyl)CON(C₃₋₆ cycloalkyl)(Heteroaryl); —N(C₃₋₆cycloalkyl)CON(Aryl)(Phenyl); —N(C₃₋₆ cycloalkyl)CON(Aryl)(Heteroaryl);—N(C₃₋₆ cycloalkyl)CON(Phenyl)(Heteroaryl); —N(Aryl)CONH₂;—N(Aryl)CONH(CH₃); N(Aryl)CON(CH₃)₂; —N(Aryl)CONH(C₂₋₆ alkyl);—N(Aryl)CON(C₂₋₆ alkyl)₂; —N(Aryl)CONHC₃₋₆ cycloalkyl; —N(Aryl)CON(C₃₋₆cycloalkyl)₂; —N(Aryl)CONHAryl; —N(Aryl)CON(Aryl)₂; —N(Aryl)CONHPhenyl;—N(Aryl)CON(Phenyl)₂; —N(Aryl)CONHHeteroaryl; —N(Aryl)CON(Heteroaryl)₂;—N(Aryl)CON(CH₃)(C₂₋₆ alkyl); —N(Aryl)CON(CH₃)(C₃₋₆ cycloalkyl);—N(Aryl)CON(CH₃)(Aryl); —N(Aryl)CON(CH₃)(Phenyl);—N(Aryl)CON(CH₃)(Heteroaryl); —N(Aryl)CON(C₂₋₆ alkyl)(C₃₋₆ cycloalkyl);—N(Aryl)CON(C₂₋₆ alkyl)(Aryl); —N(Aryl)CON(C₂₋₆ alkyl)(Phenyl);—N(Aryl)CON(C₂₋₆ alkyl)(Heteroaryl); —N(Aryl)CON(C₃₋₆ cycloalkyl)(Aryl);—N(Aryl)CON(C₃₋₆ cycloalkyl)(Phenyl); —N(Aryl)CON(C₃₋₆cycloalkyl)(Heteroaryl); —N(Aryl)CON(Aryl)(Phenyl);—N(Aryl)CON(Aryl)(Heteroaryl); —N(Aryl)CON(Phenyl)(Heteroaryl);—N(Phenyl)CONH₂; —N(Phenyl)CONH(CH₃); N(Phenyl)CON(CH₃)₂;—N(Phenyl)CONH(C₂₋₆ alkyl); —N(Phenyl)CON(C₂₋₆ alkyl)₂;—N(Phenyl)CONHC₃₋₆ cycloalkyl; —N(Phenyl)CON(C₃₋₆ cycloalkyl)₂;—N(Phenyl)CONHAryl; —N(Phenyl)CON(Aryl)₂; —N(Phenyl)CONHPhenyl;—N(Phenyl)CON(Phenyl)₂; —N(Phenyl)CONHHeteroaryl;—N(Phenyl)CON(Heteroaryl)₂; —N(Phenyl)CON(CH₃)(C₂₋₆ alkyl);—N(Phenyl)CON(CH₃)(C₃₋₆ cycloalkyl); —N(Phenyl)CON(CH₃)(Aryl);—N(Phenyl)CON(CH₃)(Phenyl); —N(Phenyl)CON(CH₃)(Heteroaryl);—N(Phenyl)CON(C₂₋₆ alkyl)(C₃₋₆ cycloalkyl); —N(Phenyl)CON(C₂₋₆alkyl)(Aryl); —N(Phenyl)CON(C₂₋₆ alkyl)(Phenyl); —N(Phenyl)CON(C₂₋₆alkyl)(Heteroaryl); —N(Phenyl)CON(C₃₋₆ cycloalkyl)(Aryl);—N(Phenyl)CON(C₃₋₆ cycloalkyl)(Phenyl); —N(Phenyl)CON(C₃₋₆cycloalkyl)(Heteroaryl); —N(Phenyl)CON(Aryl)(Phenyl);—N(Phenyl)CON(Aryl)(Heteroaryl); —N(Phenyl)CON(Phenyl)(Heteroaryl);—N(Heteroaryl)CONH₂; —N(Heteroaryl)CONH(CH₃); N(Heteroaryl)CON(CH₃)₂;—N(Heteroaryl)CONH(C₂₋₆ alkyl); —N(Heteroaryl)CON(C₂₋₆ alkyl)₂;—N(Heteroaryl)CONHC₃₋₆ cycloalkyl; —N(Heteroaryl)CON(C₃₋₆ cycloalkyl)₂;—N(Heteroaryl)CONHAryl; —N(Heteroaryl)CON(Aryl)₂;—N(Heteroaryl)CONHPhenyl; —N(Heteroaryl)CON(Phenyl)₂;—N(Heteroaryl)CONHHeteroaryl; —N(Heteroaryl)CON(Heteroaryl)₂;—N(Heteroaryl)CON(CH₃)(C₂₋₆ alkyl); —N(Heteroaryl)CON(CH₃)(C₃₋₆cycloalkyl); —N(Heteroaryl)CON(CH₃)(Aryl);—N(Heteroaryl)CON(CH₃)(Phenyl); —N(Heteroaryl)CON(CH₃)(Heteroaryl);—N(Heteroaryl)CON(C₂₋₆ alkyl)(C₃₋₆ cycloalkyl); —N(Heteroaryl)CON(C₂₋₆alkyl)(Aryl); —N(Heteroaryl)CON(C₂₋₆ alkyl)(Phenyl);—N(Heteroaryl)CON(C₂₋₆ alkyl)(Heteroaryl); —N(Heteroaryl)CON(C₃₋₆cycloalkyl)(Aryl); —N(Heteroaryl)CON(C₃₋₆ cycloalkyl)(Phenyl);—N(Heteroaryl)CON(C₃₋₆ cycloalkyl)(Heteroaryl);—N(Heteroaryl)CON(Aryl)(Phenyl); —N(Heteroaryl)CON(Aryl)(Heteroaryl);—N(Heteroaryl)CON(Phenyl)(Heteroaryl); —NHCONH(CH₃); —NHCON(CH₃)₂;—NHCONH(C₂₋₆alkyl); —NHCON(C₂₋₆alkyl)₂; —NHCON(CH₃)(C₂₋₆ alkyl); —N(C₂₋₆alkyl)CONH₂; —N(C₂₋₆ alkyl)CONH(CH₃); —N(C₂₋₆ alkyl)CON(CH₃)₂; —N(C₂₋₆alkyl)CONH(C₂₋₆ alkyl); —N(C₂₋₆ alkyl)CON(C₂₋₆ alkyl)₂; —N(C₂₋₆alkyl)CON(CH₃)(C₂₋₆ alkyl); thiocarbonyl; —C(S)CH₃; —C(S)C₂₋₆ alkyl;—C(S)C₃₋₆ cycloalkyl; —C(S)Aryl; —C(S)Phenyl; —C(S)Heteroaryl; sulfonyl;—SO₂CH₃; —SO₂C₂₋₆ alkyl; —SO₂C₃₋₆ cycloalkyl; —SO₂Aryl; —SO₂Ph;—SO₂Heteroaryl; sulfinyl; —SOCH₃; —SOC₂₋₆ alkyl; —SOC₃₋₆ cycloalkyl;—SOAryl; —SOPh; —SOHeteroaryl; sulfate; —OSO₂CH₃; —OSO₂C₂₋₆ alkyl;—OSO₂C₃₋₆ cycloalkyl; —OSO₂Aryl; —OSO₂Phenyl; —OSO₂Heteroaryl;sulfonamide; —SO₂NH₂; —SO₂NHCH₃; —SO₂NHC₂₋₆ alkyl; SO₂NHC₃₋₆ cycloalkyl;—SO₂NHAryl; —SO₂NHPh; —SO₂NHHeteroaryl; —SO₂N(CH₃)₂; —SO₂N(C₂₋₆ alkyl)₂;—SO₂N(C₃₋₆ cycloalkyl)₂; —SO₂N(Aryl)₂; —SO₂N(Ph)₂; —SO₂N(Heteroaryl)₂;—SO₂N(CH₃)(C₂₋₆ alkyl); —SO₂N(CH₃)(C₃₋₆ cycloalkyl); —SO₂N(CH₃)(Aryl);—SO₂N(CH₃)(Phenyl); —SO₂N(CH₃)(Heteroaryl); —SO₂N(C₂₋₆ alkyl)(C₃₋₆cycloalkyl); —SO₂N(C₂₋₆ alkyl)(Aryl); —SO₂N(C₂₋₆ alkyl)(Phenyl);—SO₂N(C₂₋₆ alkyl)(Heteroaryl); —SO₂N(C₃₋₆ cycloalkyl)(Aryl); —SO₂N(C₃₋₆cycloalkyl)(Phenyl); —SO₂N(C₃₋₆ cycloalkyl)(Heteroaryl);—SO₂N(Aryl)(Phenyl); —SO₂N(Aryl)(Heteroaryl); —SO₂N(Phenyl)(heteroaryl);—NHSO₂CH₃; —NHSO₂C₂₋₆ alkyl; —NHSO₂C₃₋₆ cycloalkyl; —NHSO₂Aryl;—NHSO₂Phenyl; —NHSO₂Heteroaryl; —N(CH₃)SO₂CH₃; —N(CH₃)SO₂C₂₋₆ alkyl;—N(CH₃)SO₂C₃₋₆ cycloalkyl; —N(CH₃)SO₂Aryl; —N(CH₃)SO₂Phenyl;—N(CH₃)SO₂Heteroaryl; —N(C₂₋₆ alkyl)SO₂CH₃; —N(C₂₋₆ alkyl)SO₂C₂₋₆ alkyl;—N(C₂₋₆ alkyl)SO₂C₃₋₆ cycloalkyl —N(C₂₋₆ alkyl)SO₂Aryl; —N(C₂₋₆alkyl)SO₂Phenyl; —N(C₂₋₆ alkyl)SO₂Heteroaryl; —N(C₃₋₆ cycloalkyl)SO₂CH₃;—N(C₃₋₆ cycloalkyl)SO₂C₂₋₆ alkyl; —N(C₃₋₆ cycloalkyl)SO₂C₃₋₆ cycloalkyl—N(C₃₋₆ cycloalkyl)SO₂Aryl; —N(C₃₋₆ cycloalkyl)SO₂Phenyl; —N(C₃₋₆cycloalkyl)SO₂Heteroaryl; —N(Aryl)SO₂CH₃; —N(Aryl)SO₂C₂₋₆ alkyl;N(Aryl)SO₂C₃₋₆ cycloalkyl; —N(Aryl)SO₂Aryl; —N(Aryl)SO₂Phenyl;—N(Aryl)SO₂Heteroaryl; —N(Phenyl)SO₂CH₃; —N(Phenyl)SO₂C₂₋₆ alkyl;—N(Phenyl)SO₂C₃₋₆ cycloalkyl; —N(Phenyl)SO₂Aryl; —N(Phenyl)SO₂Phenyl;—N(Phenyl)SO₂Heteroaryl; —N(Heteroaryl)SO₂CH₃; —N(Heteroaryl)SO₂C₂₋₆alkyl; —N(Heteroaryl)SO₂C₃₋₆ cycloalkyl; —N(Heteroaryl)SO₂Aryl;—N(Heteroaryl)SO₂Phenyl; —N(Heteroaryl)SO₂Heteroaryl; oxime; ═NOH;═NOCH₃; ═NOC₂₋₆alkyl; ═NOC₃₋₆cycloalkyl; ═NOAryl; ═NOPhenyl;═NOHeteroaryl; —CH═NOH; —CH═NOCH₃; —CH═NOC₂₋₆alkyl;—CH═NOC₃₋₆cycloalkyl; —CH═NOAryl; —CH═NOPhenyl; —CH═NOHeteroaryl;—C(CH₃)═NOH; —C(CH₃)═NOCH₃; —C(CH₃)═NOC₂₋₆alkyl;—C(CH₃)═NOC₃₋₆cycloalkyl; —C(CH₃)═NOAryl; —C(CH₃)═NOPhenyl;—C(CH₃)═NOHeteroaryl; —C(C₂₋₆alkyl)═NOH; —C(C₂₋₆alkyl)═NOCH₃;—C(C₂₋₆alkyl)═NOC₂₋₆alkyl; —C(C₂₋₆alkyl)═NOC₃₋₆cycloalkyl;—C(C₂₋₆alkyl)═NOAryl; —C(C₂₋₆alkyl)═NOPhenyl;—C(C₂₋₆alkyl)═NOHeteroaryl; —C(C₃₋₆cycloalkyl)═NOH;—C(C₃₋₆cycloalkyl)═NOCH₃; —C(C₃₋₆cycloalkyl)═NOC₂₋₆alkyl;—C(C₃₋₆cycloalkyl)═NOC₃₋₆cycloalkyl; —C(C₃₋₆cycloalkyl)═NOAryl;—C(C₃₋₆cycloalkyl)═NOPhenyl; —C(C₃₋₆cycloalkyl)═NOHeteroaryl;—C(Aryl)═NOH; —C(Aryl)═NOCH₃; —C(Aryl)═NOC₂₋₆alkyl;—C(Aryl)═NOC₃₋₆cycloalkyl; —C(Aryl)═NOAryl; —C(Aryl)═NOPhenyl;—C(Aryl)═NOHeteroaryl; —C(Phenyl)═NOH; —C(Phenyl)═NOCH₃;—C(Phenyl)═NOC₂₋₆alkyl; —C(Phenyl)═NOC₃₋₆cycloalkyl; —C(Phenyl)═NOAryl;—C(Phenyl)═NOPhenyl; —C(Phenyl)═NOHeteroaryl; —C(Heteroaryl)═NOH;—C(Heteroaryl)═NOCH₃; —C(Heteroaryl)═NOC₂₋₆alkyl;—C(Heteroaryl)═NOC₃₋₆cycloalkyl; —C(Heteroaryl)═NOAryl;—C(Heteroaryl)═NOPhenyl; —C(Heteroaryl)═NOHeteroaryl; —ON═CH(CH₃);—ON═CH(C₂₋₆alkyl); —ON═CH(C₃₋₆cycloalkyl); —ON═CH(Aryl); —ON═CH(Phenyl);—ON═CH(heteroaryl); —ON═C(CH₃)₂; —ON═C(CH₃)(C₂₋₆alkyl);—ON═C(CH₃)(C₃₋₆cycloalkyl); —ON═C(CH₃)(Aryl); —ON═C(CH₃)(Phenyl);—ON═C(CH₃)(heteroaryl); —ON═C(C₂₋₆alkyl)₂; —ON═C(C₂₋₆alkyl)(C₃₋₆cycloalkyl); —ON═C(C₂₋₆alkyl)(Aryl); —ON═C(C₂₋₆alkyl)(Phenyl);—ON═C(C₂₋₆alkyl)(Heteroaryl); —ON═C(C₃₋₆cycloalkyl)₂;—ON═C(C₃₋₆cycloalkyl)(Aryl); —ON═C(C₃₋₆cycloalkyl)(Phenyl);—ON═C(C₃₋₆cycloalkyl)(Heteroaryl); —ON═C(Aryl)₂; —ON═C(Aryl)(Phenyl);—ON═C(Aryl)(Heteroaryl); —ON═C(Phenyl)₂; —ON═C(Phenyl)(Heteroaryl);—ON═C(Heteroaryl)₂; imine; ═NH; ═NCH₃; ═NC₂₋₆alkyl; ═NC₃₋₆cycloalkyl;═NAryl; ═NPhenyl; ═NHeteroaryl; —CH═NH; —CH═NCH₃; —CH═NC₂₋₆alkyl;—CH═NC₃₋₆cycloalkyl; —CH═NAryl; —CH═NPhenyl; —CH═NHeteroaryl;—C(CH₃)═NH; —C(CH₃)═NCH₃; —C(CH₃)═NC₂₋₆alkyl; —C(CH₃)═NC₃₋₆cycloalkyl;—C(CH₃)═NAryl; —C(CH₃)═NPhenyl; —C(CH₃)═NHeteroaryl; —C(C₂₋₆alkyl)═NH;—C(C₂₋₆alkyl)═NCH₃; —C(C₂₋₆alkyl)═NC₂₋₆alkyl;—C(C₂₋₆alkyl)═NC₃₋₆cycloalkyl; —C(C₂₋₆alkyl)═NAryl;—C(C₂₋₆alkyl)═NPhenyl; —C(C₂₋₆alkyl)═NHeteroaryl; —C(C₃₋₆cycloalkyl)═NH;—C(C₃₋₆cycloalkyl)═NCH₃; —C(C₃₋₆cycloalkyl)═NC₂₋₆alkyl;—C(C₃₋₆cycloalkyl)═NC₃₋₆cycloalkyl; —C(C₃₋₆cycloalkyl)═NAryl;—C(C₃₋₆cycloalkyl)═NPhenyl; —C(C₃₋₆cycloalkyl)═NHeteroaryl; —C(Aryl)═NH;—C(Aryl)═NCH₃; —C(Aryl)═NC₂₋₆alkyl; —C(Aryl)═NC₃₋₆cycloalkyl;—C(Aryl)═NAryl; —C(Aryl)═NPhenyl; —C(Aryl)═NHeteroaryl; —C(Phenyl)═NH;—C(Phenyl)═NCH₃; —C(Phenyl)═NC₂₋₆alkyl; —C(Phenyl)═NC₃₋₆cycloalkyl;—C(Phenyl)═NAryl; —C(Phenyl)═NPhenyl; —C(Phenyl)═NHeteroaryl;—C(Heteroaryl)═NH; —C(Heteroaryl)═NCH₃; —C(Heteroaryl)═NC₂₋₆alkyl;—C(Heteroaryl)═NC₃₋₆cycloalkyl; —C(Heteroaryl)═NAryl;—C(Heteroaryl)═NPhenyl; —C(Heteroaryl)═NHeteroaryl; —N═CH(CH₃);—N═CH(C₂₋₆alkyl); —N═CH(C₃₋₆cycloalkyl); —N═CH(Aryl); —N═CH(Phenyl);—N═CH(heteroaryl); —N═C(CH₃)₂; —N═C(CH₃)(C₂₋₆alkyl);—N═C(CH₃)(C₃₋₆cycloalkyl); —N═C(CH₃)(Aryl); —N═C(CH₃)(Phenyl);—N═C(CH₃)(heteroaryl); —N═C(C₂₋₆alkyl)₂; —N═C(C₂₋₆alkyl)(C₃₋₆cycloalkyl); —N═C(C₂₋₆alkyl)(Aryl); —N═C(C₂₋₆alkyl)(Phenyl);—N═C(C₂₋₆alkyl)(Heteroaryl); —N═C(C₃₋₆cycloalkyl)₂;—N═C(C₃₋₆cycloalkyl)(Aryl); —N═C(C₃₋₆cycloalkyl)(Phenyl);—N═C(C₃₋₆cycloalkyl)(Heteroaryl); —N═C(Aryl)₂; —N═C(Aryl)(Phenyl);—N═C(Aryl)(Heteroaryl); —N═C(Phenyl)₂; —N═C(Phenyl)(Heteroaryl);—N═C(Heteroaryl)₂; ketone; acetyl; —C(O)CH₃; —C(O)C₂₋₆alkyl;—C(O)C₃₋₆cycloalkyl; —C(O)Aryl; —C(O)Phenyl; —C(O)Heteroaryl;—CH₂C(O)CH₃; —CH₂C(O)C₂₋₆alkyl; —CH₂C(O)C₃₋₆cycloalkyl; —CH₂C(O)Aryl;—CH₂C(O)Phenyl; —CH₂C(O)Heteroaryl; —C₂₋₆alkyl C(O)C₂₋₆alkyl;—C₂₋₆alkylC(O)C₃₋₆cycloalkyl; —C₂₋₆alkyl C(O)Aryl; —C₂₋₆alkylC(O)Phenyl;—C₂₋₆alkylC(O)Heteroaryl; —C(O)CH₂CH₃; —C(O)CH₂C₂₋₆alkyl;—C(O)CH₂C₃₋₆cycloalkyl; —C(O)CH₂Aryl; —C(O)CH₂Phenyl;—C(O)CH₂Heteroaryl; —C(O)C₂₋₆alkylCH₃; —C(O)C₂₋₆alkylC₂₋₆alkyl;—C(O)C₂₋₆alkyC₃₋₆cycloalkyl; —C(O)C₂₋₆alkylAryl; —C(O)C₂₋₆alkylPhenyl;—C(O)C₂₋₆alkyl Heteroaryl; aldehyde; —CHO; —CH₂CHO; —C₂₋₆alkylCHO;ester; —CO₂CH₃; —CO₂C₂₋₆alkyl; —CO₂C₃₋₆cycloalkyl; —CO₂Aryl; —CO₂Phenyl;—CO₂Heteroaryl; reverse ester; acetoxy; —OCOCH₃; —OCOC₂₋₆alkyl;—OCOC₃₋₆cycloalkyl; —OCOAryl; —OCOPhenyl; —OCOHeteroaryl; oxygen (═O);hydrazinyl; —NHNH₂; —N(CH₃)NH₂; —N(C₂₋₆alkyl)NH₂; —N(C₃₋₆cycloalkyl)NH₂;—N(Aryl)NH₂; —N(Phenyl)NH₂; —N(Heteroaryl)NH₂; —N(COCH₃)NH₂;—N(COC₂₋₆alkyl)NH₂; —N(COC₃₋₆cycloalkyl)NH₂; —N(COAryl)NH₂;—N(COPhenyl)NH₂; —N(COHeteroaryl)NH₂; —NHNH(CH₃); —NHNH(C₂₋₆alkyl);—NHNH(C₃₋₆cycloalkyl); —NHNH(Aryl); —NHNH(Phenyl); —NHNH(Heteroaryl);—NHNH(COCH₃); —NHNH(COC₂₋₆alkyl); —NHNH(COC₃₋₆cycloalkyl);—NHNH(COAryl); —NHNH(COPhenyl); —NHNH(COHeteroaryl); —N(CH₃)NH(CH₃);—N(CH₃)NH(C₂₋₆alkyl); —N(CH₃)NH(C₃₋₆cycloalkyl); —N(CH₃)NH(Aryl);—N(CH₃)NH(Phenyl); —N(CH₃)NH(Heteroaryl); —N(CH₃)NH(COCH₃);—N(CH₃)NH(COC₂₋₆alkyl); —N(CH₃)NH(COC₃₋₆cycloalkyl); —N(CH₃)NH(COAryl);—N(CH₃)NH(COPhenyl); —N(CH₃)NH(COHeteroaryl); —N(C₂₋₆alkyl)NH(CH₃);—N(C₂₋₆alkyl)NH(C₂₋₆alkyl); —N(C₂₋₆alkyl)NH(C₃₋₆cycloalkyl);—N(C₂₋₆alkyl)NH(Aryl); —N(C₂₋₆alkyl)NH(Phenyl);—N(C₂₋₆alkyl)NH(Heteroaryl); —N(C₂₋₆alkyl)NH(COCH₃);—N(C₂₋₆alkyl)NH(COC₂₋₆alkyl); —N(C₂₋₆alkyl)NH(COC₃₋₆cycloalkyl);—N(C₂₋₆alkyl)NH(COAryl); —N(C₂₋₆alkyl)NH(COPhenyl);—N(C₂₋₆alkyl)NH(COHeteroaryl); —N(C₃₋₆cycloalkyl)NH(CH₃);—N(C₃₋₆cycloalkyl)NH(C₂₋₆alkyl); —N(C₃₋₆cycloalkyl)NH(C₃₋₆cycloalkyl);—N(C₃₋₆cycloalkyl)NH(Aryl); —N(C₃₋₆cycloalkyl)NH(Phenyl);—N(C₃₋₆cycloalkyl)NH(Heteroaryl); —N(C₃₋₆cycloalkyl)NH(COCH₃);—N(C₃₋₆cycloalkyl)NH(COC₂₋₆alkyl);—N(C₃₋₆cycloalkyl)NH(COC₃₋₆cycloalkyl); —N(C₃₋₆cycloalkyl)NH(COAryl);—N(C₃₋₆cycloalkyl)NH(COPhenyl); —N(C₃₋₆cycloalkyl)NH(COHeteroaryl);—N(Aryl)NH(CH₃); —N(Aryl)NH(C₂₋₆alkyl); —N(Aryl)NH(C₃₋₆cycloalkyl);—N(Aryl)NH(Aryl); —N(Aryl)NH(Phenyl); —N(Aryl)NH(Heteroaryl);—N(Aryl)NH(COCH₃); —N(Aryl)NH(COC₂₋₆alkyl);—N(Aryl)NH(COC₃₋₆cycloalkyl); —N(Aryl)NH(COAryl); —N(Aryl)NH(COPhenyl);—N(Aryl)NH(COHeteroaryl); —N(Phenyl)NH(CH₃); —N(Phenyl)NH(C₂₋₆alkyl);—N(Phenyl)NH(C₃₋₆cycloalkyl); —N(Phenyl)NH(Aryl); —N(Phenyl)NH(Phenyl);—N(Phenyl)NH(Heteroaryl); —N(Phenyl)NH(COCH₃);—N(Phenyl)NH(COC₂₋₆alkyl); —N(Phenyl)NH(COC₃₋₆cycloalkyl);—N(Phenyl)NH(COAryl); —N(Phenyl)NH(COPhenyl);—N(Phenyl)NH(COHeteroaryl); —N(Heteroaryl)NH(CH₃);—N(Heteroaryl)NH(C₂₋₆alkyl); —N(Heteroaryl)NH(C₃₋₆cycloalkyl);—N(Heteroaryl)NH(Aryl); —N(Heteroaryl)NH(Phenyl);—N(Heteroaryl)NH(Heteroaryl); —N(Heteroaryl)NH(COCH₃);—N(Heteroaryl)NH(COC₂₋₆alkyl); —N(Heteroaryl)NH(COC₃₋₆cycloalkyl);—N(Heteroaryl)NH(COAryl); —N(Heteroaryl)NH(COPhenyl);—N(Heteroaryl)NH(COHeteroaryl); —N(COCH₃)NH(CH₃);—N(COCH₃)NH(C₂₋₆alkyl); —N(COCH₃)NH(C₃₋₆cycloalkyl); —N(COCH₃)NH(Aryl);—N(COCH₃)NH(Phenyl); —N(COCH₃)NH(Heteroaryl); —N(COCH₃)NH(COCH₃);—N(COCH₃)NH(COC₂₋₆alkyl); —N(COCH₃)NH(COC₃₋₆cycloalkyl);—N(COCH₃)NH(COAryl); —N(COCH₃)NH(COPhenyl); —N(COCH₃)NH(COHeteroaryl);—N(COC₂₋₆alkyl)NH(CH₃); —N(COC₂₋₆alkyl)NH(C₂₋₆alkyl);—N(COC₂₋₆alkyl)NH(C₃₋₆cycloalkyl); —N(COC₂₋₆alkyl)NH(Aryl);—N(COC₂₋₆alkyl)NH(Phenyl); —N(COC₂₋₆alkyl)NH(Heteroaryl);—N(COC₂₋₆alkyl)NH(COCH₃); —N(COC₂₋₆alkyl)NH(COC₂₋₆alkyl);—N(COC₂₋₆alkyl)NH(COC₃₋₆cycloalkyl); —N(COC₂₋₆alkyl)NH(COAryl);—N(COC₂₋₆alkyl)NH(COPhenyl); —N(COC₂₋₆alkyl)NH(COHeteroaryl);—N(COC₃₋₆cycloalkyl)NH(CH₃); —N(COC₃₋₆cycloalkyl)NH(C₂₋₆alkyl);—N(COC₃₋₆cycloalkyl)NH(C₃₋₆cycloalkyl); —N(COC₃₋₆cycloalkyl)NH(Aryl);—N(COC₃₋₆cycloalkyl)NH(Phenyl); —N(COC₃₋₆cycloalkyl)NH(Heteroaryl);—N(COC₃₋₆cycloalkyl)NH(COCH₃); —N(COC₃₋₆cycloalkyl)NH(COC₂₋₆alkyl);—N(COC₃₋₆cycloalkyl)NH(COC₃₋₆cycloalkyl);—N(COC₃₋₆cycloalkyl)NH(COAryl); —N(COC₃₋₆cycloalkyl)NH(COPhenyl);—N(COC₃₋₆cycloalkyl)NH(COHeteroaryl); —N(COAryl)NH(CH₃);—N(COAryl)NH(C₂₋₆alkyl); —N(COAryl)NH(C₃₋₆cycloalkyl);—N(COAryl)NH(Aryl); —N(COAryl)NH(Phenyl); —N(COAryl)NH(Heteroaryl);—N(COAryl)NH(COCH₃); —N(COAryl)NH(COC₂₋₆alkyl);—N(COAryl)NH(COC₃₋₆cycloalkyl); —N(COAryl)NH(COAryl);—N(COAryl)NH(COPhenyl); —N(COAryl)NH(COHeteroaryl); —N(COPhenyl)NH(CH₃);—N(COPhenyl)NH(C₂₋₆alkyl); —N(COPhenyl)NH(C₃₋₆cycloalkyl);—N(COPhenyl)NH(Aryl); —N(COPhenyl)NH(Phenyl);—N(COPhenyl)NH(Heteroaryl); —N(COPhenyl)NH(COCH₃);—N(COPhenyl)NH(COC₂₋₆alkyl); —N(COPhenyl)NH(COC₃₋₆cycloalkyl);—N(COPhenyl)NH(COAryl); —N(COPhenyl)NH(COPhenyl);—N(COPhenyl)NH(COHeteroaryl); —N(COHeteroaryl)NH(CH₃);—N(COHeteroaryl)NH(C₂₋₆alkyl); —N(COHeteroaryl)NH(C₃₋₆cycloalkyl);—N(COHeteroaryl)NH(Aryl); —N(COHeteroaryl)NH(Phenyl);—N(COHeteroaryl)NH(Heteroaryl); —N(COHeteroaryl)NH(COCH₃);—N(COHeteroaryl)NH(COC₂₋₆alkyl); —N(COHeteroaryl)NH(COC₃₋₆cycloalkyl);—N(COHeteroaryl)NH(COAryl); —N(COHeteroaryl)NH(COPhenyl);—N(COHeteroaryl)NH(COHeteroaryl); —NHN(CH₃)₂; —NHN(CH₃)(C₂₋₆alkyl);—NHN(CH₃)(C₃₋₆cycloalkyl); —NHN(CH₃)(Aryl); —NHN(CH₃)(Phenyl);—NHN(CH₃)(Heteroaryl); —NHN(CH₃)(COCH₃); —NHN(CH₃)(COC₂₋₆alkyl);—NHN(CH₃)(COC₃₋₆cycloalkyl); —NHN(CH₃)(COAryl); —NHN(CH₃)(COPhenyl);—NHN(CH₃)(COHeteroaryl); —NHN(C₂₋₆alkyl)₂;—NHN(C₂₋₆alkyl)(C₃₋₆cycloalkyl); —NHN(C₂₋₆alkyl)(Aryl);—NHN(C₂₋₆alkyl)(Phenyl); —NHN(C₂₋₆alkyl)(Heteroaryl);—NHN(C₂₋₆alkyl)(COCH₃); —NHN(C₂₋₆alkyl)(COC₂₋₆alkyl);—NHN(C₂₋₆alkyl)(COC₃₋₆cycloalkyl); —NHN(C₂₋₆alkyl)(COAryl);—NHN(C₂₋₆alkyl)(COPhenyl); —NHN(C₂₋₆alkyl)(COHeteroaryl);—NHN(C₃₋₆cycloalkyl)₂; —NHN(C₃₋₆cycloalkyl)(Aryl);—NHN(C₃₋₆cycloalkyl)(Phenyl); —NHN(C₃₋₆cycloalkyl)(Heteroaryl);—NHN(C₃₋₆cycloalkyl)(COCH₃); —NHN(C₃₋₆cycloalkyl)(COC₂₋₆alkyl);—NHN(C₃₋₆cycloalkyl)(COC₃₋₆cycloalkyl); —NHN(C₃₋₆cycloalkyl)(COAryl);—NHN(C₃₋₆cycloalkyl)(COPhenyl); —NHN(C₃₋₆cycloalkyl)(COHeteroaryl);—NHN(Ary)₂; —NHN(Aryl)(Phenyl); —NHN(Ary)(Heteroaryl);—NHN(Aryl)(COCH₃); —NHN(Aryl)(COC₂₋₆alkyl);—NHN(Aryl)(COC₃₋₆cycloalkyl); —NHN(Aryl)(COAryl); —NHN(Aryl)(COPhenyl);—NHN(Ary)(COHeteroaryl); —NHN(Phenyl)₂; —NHN(Phenyl)(Heteroaryl);—NHN(Phenyl)(COCH₃); —NHN(Phenyl)(COC₂₋₆alkyl);—NHN(Phenyl)(COC₃₋₆cycloalkyl); —NHN(Phenyl)(COAryl);—NHN(Phenyl)(COPhenyl); —NHN(Phenyl)(COHeteroaryl); —NHN(Heteroaryl)₂;—NHN(Heteroaryl)(COCH₃); —NHN(Heteroaryl)(COC₂₋₆alkyl);—NHN(Heteroaryl)(COC₃₋₆cycloalkyl); —NHN(Heteroaryl)(COAryl);—NHN(Heteroaryl)(COPhenyl); —NHN(Heteroaryl)(COHeteroaryl);—NHN(COCH₃)₂; —NHN(COCH₃)(COC₂₋₆alkyl); —NHN(COCH₃)(COC₃₋₆cycloalkyl);—NHN(COCH₃)(COAryl); —NHN(COCH₃)(COPhenyl); —NHN(COCH₃)(COHeteroaryl);—NHN(COC₂₋₆alkyl)₂; —NHN(COC₂₋₆alkyl)(COC₃₋₆cycloalkyl);—NHN(COC₂₋₆alkyl)(COAryl); —NHN(COC₂₋₆alkyl)(COPhenyl);—NHN(COC₂₋₆alkyl)(COHeteroaryl); —NHN(COC₃₋₆cycloalkyl)₂;—NHN(COC₃₋₆cycloalkyl)(COAryl); —NHN(COC₃₋₆cycloalkyl)(COPhenyl);—NHN(COC₃₋₆cycloalkyl)(COHeteroaryl); —NHN(COAryl)₂;—NHN(COAryl)(COPhenyl); —NHN(COAryl)(COHeteroaryl); —NHN(COPhenyl)₂;—NHN(COPhenyl)(COHeteroaryl); —NHN(COHeteroaryl)₂; —N(CH₃)N(CH₃)₂;—N(CH₃)N(CH₃)(C₂₋₆alkyl); —N(CH₃)N(CH₃)(C₃₋₆cycloalkyl);—N(CH₃)N(CH₃)(Aryl); —N(CH₃)N(CH₃)(Phenyl); —N(CH₃)N(CH₃)(Heteroaryl);—N(CH₃)N(CH₃)(COCH₃); —N(CH₃)N(CH₃)(COC₂₋₆alkyl);—N(CH₃)N(CH₃)(COC₃₋₆cycloalkyl); —N(CH₃)N(CH₃)(COAryl);—N(CH₃)N(CH₃)(COPhenyl); —N(CH₃)N(CH₃)(COHeteroaryl);—N(CH₃)N(C₂₋₆alkyl)₂; —N(CH₃)N(C₂₋₆alkyl)(C₃₋₆cycloalkyl);—N(CH₃)N(C₂₋₆alkyl)(Aryl); —N(CH₃)N(C₂₋₆alkyl)(Phenyl);—N(CH₃)N(C₂₋₆alkyl)(Heteroaryl); —N(CH₃)N(C₂₋₆alkyl)(COCH₃);—N(CH₃)N(C₂₋₆alkyl)(COC₂₋₆alkyl); —N(CH₃)N(C₂₋₆alkyl)(COC₃₋₆cycloalkyl);—N(CH₃)N(C₂₋₆alkyl)(COAryl); —N(CH₃)N(C₂₋₆alkyl)(COPhenyl);—N(CH₃)N(C₂₋₆alkyl)(COHeteroaryl); —N(CH₃)N(C₃₋₆cycloalkyl)₂;—N(CH₃)N(C₃₋₆cycloalkyl)(Aryl); —N(CH₃)N(C₃₋₆cycloalkyl)(Phenyl);—N(CH₃)N(C₃₋₆cycloalkyl)(Heteroaryl); —N(CH₃)N(C₃₋₆cycloalkyl)(COCH₃);—N(CH₃)N(C₃₋₆cycloalkyl)(COC₂₋₆alkyl);—N(CH₃)N(C₃₋₆cycloalkyl)(COC₃₋₆cycloalkyl);—N(CH₃)N(C₃₋₆cycloalkyl)(COAryl); —N(CH₃)N(C₃₋₆cycloalkyl)(COPhenyl);—N(CH₃)N(C₃₋₆cycloalkyl)(COHeteroaryl); —N(CH₃)N(Aryl)₂;—N(CH₃)N(Aryl)(Phenyl); —N(CH₃)N(Aryl)(Heteroaryl);—N(CH₃)N(Aryl)(COCH₃); —N(CH₃)N(Aryl)(COC₂₋₆alkyl);—N(CH₃)N(Aryl)(COC₃₋₆cycloalkyl); —N(CH₃)N(Aryl)(COAryl);—N(CH₃)N(Aryl)(COPhenyl); —N(CH₃)N(Aryl)(COHeteroaryl);—N(CH₃)N(Phenyl)₂; —N(CH₃)N(Phenyl)(Heteroaryl);—N(CH₃)N(Phenyl)(COCH₃); —N(CH₃)N(Phenyl)(COC₂₋₆alkyl);—N(CH₃)N(Phenyl)(COC₃₋₆cycloalkyl); —N(CH₃)N(Phenyl)(COAryl);—N(CH₃)N(Phenyl)(COPhenyl); —N(CH₃)N(Phenyl)(COHeteroaryl);—N(CH₃)N(Heteroaryl)₂; —N(CH₃)N(Heteroaryl)(COCH₃);—N(CH₃)N(Heteroaryl)(COC₂₋₆alkyl);—N(CH₃)N(Heteroaryl)(COC₃₋₆cycloalkyl); —N(CH₃)N(Heteroaryl)(COAryl);—N(CH₃)N(Heteroaryl)(COPhenyl); —N(CH₃)N(Heteroaryl)(COHeteroaryl);—N(CH₃)N(COCH₃)₂; —N(CH₃)N(COCH₃)(COC₂₋₆alkyl);—N(CH₃)N(COCH₃)(COC₃₋₆cycloalkyl); —N(CH₃)N(COCH₃)(COAryl);—N(CH₃)N(COCH₃)(COPhenyl); —N(CH₃)N(COCH₃)(COHeteroaryl);—N(CH₃)N(COC₂₋₆alkyl)₂; —N(CH₃)N(COC₂₋₆alkyl)(COC₃₋₆cycloalkyl);—N(CH₃)N(COC₂₋₆alkyl)(COAryl); —N(CH₃)N(COC₂₋₆alkyl)(COPhenyl);—N(CH₃)N(COC₂₋₆alkyl)(COHeteroaryl); —N(CH₃)N(COC₃₋₆cycloalkyl)₂;—N(CH₃)N(COC₃₋₆cycloalkyl)(COAryl);—N(CH₃)N(COC₃₋₆cycloalkyl)(COPhenyl);—N(CH₃)N(COC₃₋₆cycloalkyl)(COHeteroaryl); —N(CH₃)N(COAryl)₂;—N(CH₃)N(COAryl)(OAryl)(COPhenyl); —N(CH₃)N(COAryl)(COHeteroaryl);—N(CH₃)N(COPhenyl)₂; —N(CH₃)N(COPhenyl)(COHeteroaryl);—N(CH₃)N(COHeteroaryl)₂; —N(Phenyl)N(CH₃)₂; —N(Phenyl)N(CH₃)(C₂₋₆alkyl);—N(Phenyl)N(CH₃)(C₃₋₆cycloalkyl); —N(Phenyl)N(CH₃)(Aryl);—N(Phenyl)N(CH₃)(Phenyl); —N(Phenyl)N(CH₃)(Heteroaryl);—N(Phenyl)N(CH₃)(COCH₃); —N(Phenyl)N(CH₃)(COC₂₋₆alkyl);—N(Phenyl)N(CH₃)(COC₃₋₆cycloalkyl); —N(Phenyl)N(CH₃)(COAryl);—N(Phenyl)N(CH₃)(COPhenyl); —N(Phenyl)N(CH₃)(COHeteroaryl);—N(Phenyl)N(C₂₋₆alkyl)₂; —N(Phenyl)N(C₂₋₆alkyl)(C₃₋₆cycloalkyl);—N(Phenyl)N(C₂₋₆alkyl)(Aryl); —N(Phenyl)N(C₂₋₆alkyl)(Phenyl);—N(Phenyl)N(C₂₋₆alkyl)(Heteroaryl); —N(Phenyl)N(C₂₋₆alkyl)(COCH₃);—N(Phenyl)N(C₂₋₆alkyl)(COC₂₋₆alkyl);—N(Phenyl)N(C₂₋₆alkyl)(COC₃₋₆cycloalkyl);—N(Phenyl)N(C₂₋₆alkyl)(COAryl); —N(Phenyl)N(C₂₋₆alkyl)(COPhenyl);—N(Phenyl)N(C₂₋₆alkyl)(COHeteroaryl); —N(Phenyl)N(C₃₋₆cycloalkyl)₂;—N(Phenyl)N(C₃₋₆cycloalkyl)(Aryl); —N(Phenyl)N(C₃₋₆cycloalkyl)(Phenyl);—N(Phenyl)N(C₃₋₆cycloalkyl)(Heteroaryl);—N(Phenyl)N(C₃₋₆cycloalkyl)(COCH₃);—N(Phenyl)N(C₃₋₆cycloalkyl)(COC₂₋₆alkyl);—N(Phenyl)N(C₃₋₆cycloalkyl)(COC₃₋₆cycloalkyl);—N(Phenyl)N(C₃₋₆cycloalkyl)(COAryl);—N(Phenyl)N(C₃₋₆cycloalkyl)(COPhenyl);—N(Phenyl)N(C₃₋₆cycloalkyl)(COHeteroaryl); —N(Phenyl)N(Aryl)₂;—N(Phenyl)N(Aryl)(Phenyl); —N(Phenyl)N(Aryl)(Heteroaryl);—N(Phenyl)N(Aryl)(COCH₃); —N(Phenyl)N(Aryl)(COC₂₋₆alkyl);—N(Phenyl)N(Aryl)(COC₃₋₆cycloalkyl); —N(Phenyl)N(Aryl)(COAryl);—N(Phenyl)N(Aryl)(COPhenyl); —N(Phenyl)N(Aryl)(COHeteroaryl);—N(Phenyl)N(Phenyl)₂; —N(Phenyl)N(Phenyl)(Heteroaryl);—N(Phenyl)N(Phenyl)(COCH₃); —N(Phenyl)N(Phenyl)(COC₂₋₆alkyl);—N(Phenyl)N(Phenyl)(COC₃₋₆cycloalkyl); —N(Phenyl)N(Phenyl)(COAryl);—N(Phenyl)N(Phenyl)(COPhenyl); —N(Phenyl)N(Phenyl)(COHeteroaryl);—N(Phenyl)N(Heteroaryl)₂; —N(Phenyl)N(Heteroaryl)(COCH₃);—N(Phenyl)N(Heteroaryl)(COC₂₋₆alkyl);—N(Phenyl)N(Heteroaryl)(COC₃₋₆cycloalkyl);—N(Phenyl)N(Heteroaryl)(COAryl); —N(Phenyl)N(Heteroaryl)(COPhenyl);—N(Phenyl)N(Heteroaryl)(COHeteroaryl); —N(Phenyl)N(COCH₃)₂;—N(Phenyl)N(COCH₃)(COC₂₋₆alkyl); —N(Phenyl)N(COCH₃)(COC₃₋₆cycloalkyl);—N(Phenyl)N(COCH₃)(COAryl); —N(Phenyl)N(COCH₃)(COPhenyl);—N(Phenyl)N(COCH₃)(COHeteroaryl); —N(Phenyl)N(COC₂₋₆alkyl)₂;—N(Phenyl)N(COC₂₋₆alkyl)(COC₃₋₆cycloalkyl);—N(Phenyl)N(COC₂₋₆alkyl(COAryl); —N(Phenyl)N(COC₂₋₆alkyl)(COPhenyl);—N(Phenyl)N(COC₂₋₆alkyl)(COHeteroaryl); —N(Phenyl)N(COC₃₋₆cycloalkyl)₂;—N(Phenyl)N(COC₃₋₆cycloalkyl)(COAryl);—N(Phenyl)N(COC₃₋₆cycloalkyl)(COPhenyl);—N(Phenyl)N(COC₃₋₆cycloalkyl)(COHeteroaryl); —N(Phenyl)N(COAryl)₂;—N(Phenyl)N(COAryl)(COPhenyl); —N(Phenyl)N(COAryl)(COHeteroaryl);—N(Phenyl)N(COPhenyl)₂; —N(Phenyl)N(COPhenyl)(COHeteroaryl);—N(Phenyl)N(COHeteroaryl)₂; hydrazonyl; ═NNH₂; ═NNH(CH₃);═NNH(C₂₋₆alkyl); ═NNH(C₃₋₆cycloalkyl); ═NNH(Aryl); ═NNH(Phenyl);═NNH(Heteroaryl); ═NNH(COCH₃); ═NNH(COC₂₋₆alkyl);═NNH(COC₃₋₆cycloalkyl); ═NNH(COAryl); ═NNH(COPhenyl);═NNH(COHeteroaryl); ═NN(CH₃)₂; ═NN(CH₃)(C₂₋₆alkyl);═NN(CH₃)(C₃₋₆cycloalkyl); ═NN(CH₃)(Aryl); ═NN(CH₃)(Phenyl);═NN(CH₃)(Heteroaryl); ═NN(CH₃)(COCH₃); ═NN(CH₃)(COC₂₋₆alkyl);═NN(CH₃)(COC₃₋₆cycloalkyl); ═NN(CH₃)(COAryl); ═NN(CH₃)(COPhenyl);═NN(CH₃)(COHeteroaryl); ═NN(C₂₋₆alkyl)₂; ═NN(C₂₋₆alkyl)(C₃₋₆cycloalkyl);═NN(C₂₋₆alkyl)(Aryl); ═NN(C₂₋₆alkyl)(Phenyl);═NN(C₂₋₆alkyl)(Heteroaryl); ═NN(C₂₋₆alkyl)(COCH₃);═NN(C₂₋₆alkyl)(COC₂₋₆alkyl); ═NN(C₂₋₆alkyl)(COC₃₋₆cycloalkyl);═NN(C₂₋₆alkyl)(COAryl); ═NN(C₂₋₆alkyl)(COPhenyl);═NN(C₂₋₆alkyl)(COHeteroaryl); ═NN(C₃₋₆cycloalkyl)₂;═NN(C₃₋₆cycloalkyl)(Aryl); ═NN(C₃₋₆cycloalkyl)(Phenyl);═NN(C₃₋₆cycloalkyl)(Heteroaryl); ═NN(C₃₋₆cycloalkyl)(COCH₃);═NN(C₃₋₆cycloalkyl)(COC₂₋₆alkyl); ═NN(C₃₋₆cycloalkyl)(COC₃₋₆cycloalkyl);═NN(C₃₋₆cycloalkyl)(COAryl); ═NN(C₃₋₆cycloalkyl)(COPhenyl);═NN(C₃₋₆cycloalkyl)(COHeteroaryl); ═NN(Aryl)₂; ═NN(Aryl)(Phenyl);═NN(Aryl)(Heteroaryl); ═NN(Aryl)(COCH₃); ═NN(Aryl)(COC₂₋₆alkyl);═NN(Aryl)(COC₃₋₆cycloalkyl); ═NN(Aryl)(COAryl); ═NN(Aryl)(COPhenyl);═NN(Aryl)(COHeteroaryl); ═NN(Phenyl)₂; ═NN(Phenyl)(Heteroaryl);═NN(Phenyl)(COCH₃); ═NN(Phenyl)(COC₂₋₆alkyl);═NN(Phenyl)(COC₃₋₆cycloalkyl); ═NN(Phenyl)(COAryl);═NN(Phenyl)(COPhenyl); ═NN(Phenyl)(COHeteroaryl); ═NN(Heteroaryl)₂;═NN(Heteroaryl)(COCH₃); ═NN(Heteroaryl)(COC₂₋₆alkyl);═NN(Heteroaryl)(COC₃₋₆cycloalkyl); ═NN(Heteroaryl)(COAryl);═NN(Heteroaryl)(COPhenyl); ═NN(Heteroaryl)(COHeteroaryl); ═NN(COCH₃)₂;═NN(COCH₃)(COC₂₋₆alkyl); ═NN(COCH₃)(COC₃₋₆cycloalkyl);═NN(COCH₃)(COAryl); ═NN(COCH₃)(COPhenyl); ═NN(COCH₃)(COHeteroaryl);═NN(COC₂₋₆alkyl)₂; ═NN(COC₂₋₆alkyl)(COC₃₋₆cycloalkyl);═NN(COC₂₋₆alkyl)(COAryl); ═NN(COC₂₋₆alkyl)(COPhenyl);═NN(COC₂₋₆alkyl)(COHeteroaryl); ═NN(COC₃₋₆cycloalkyl)₂;═NN(COC₃₋₆cycloalkyl)(COAryl); ═NN(COC₃₋₆cycloalkyl)(COPhenyl);═NN(COC₃₋₆cycloalkyl)(COHeteroaryl); ═NN(COAryl)₂;═NN(COAryl)(COPhenyl); ═NN(COAryl)(COHeteroaryl); ═NN(COPhenyl)₂;═NN(COPhenyl)(COHeteroaryl); ═NN(COHeteroaryl)₂; haloalkyl (e.g.,trifluoromethyl, difluoromethyl, fluoromethyl); substituted aminoacyland aminoalkyl; carbocyclic C₃₋₈ cycloalkyl, which may be monocyclic orfused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl), or a heterocycloalkyl, which may bemonocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, furanyl, or thiazinyl);carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclicaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl,pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl, orbenzofuranyl); —O-aryl; aryl; aryl-C_(1- or 2-6)alkyl; alkoxy; —OCH₃;—OC₂₋₆alkyl; —OC₃₋₆cycloalkyl; —OPhenyl; —OPhenyl-C_(1- or 2-6)alkyl;—OHeteroaryl; —CO₂CH₃; —CONH₂; —OCH₂CONH₂; —NH₂; —N(C₁₋₄alkyl)₂; amido;—NHC(O)CH₃; —NHC(O)C₂₋₆alkyl; —NHC(O)C₃₋₆cycloalkyl; —NHC(O)Aryl;—NHC(O)Phenyl; —NHC(O)Heteroaryl; —N(CH₃)C(O)CH₃; —N(CH₃)C(O)C₂₋₆alkyl;—N(CH₃)C(O)C₃₋₆cycloalkyl; —N(CH₃)C(O)Aryl; —N(CH₃)C(O)Phenyl;—N(CH₃)C(O)Heteroaryl; —N(C₂₋₆alkyl)C(O)CH₃; —N(C₂₋₆alkyl)C(O)C₂₋₆alkyl;—N(C₂₋₆alkyl)C(O)C₃₋₆cycloalkyl; —N(C₂₋₆alkyl)C(O)Aryl;—N(C₂₋₆alkyl)C(O)Phenyl; —N(C₂₋₆alkyl)C(O)Heteroaryl;—N(C₃₋₆cycloalkyl)C(O)CH₃; —N(C₃₋₆cycloalkyl)C(O)C₂₋₆alkyl;—N(C₃₋₆cycloalkyl)C(O)C₃₋₆cycloalkyl; —N(C₃₋₆cycloalkyl)C(O)Aryl;—N(C₃₋₆cycloalkyl)C(O)Phenyl; —N(C₃₋₆cycloalkyl)C(O)Heteroaryl;—N(Aryl)C(O)CH₃; —N(Aryl)C(O)C₂₋₆alkyl; —N(Aryl)C(O)C₃₋₆cycloalkyl;—N(Aryl)C(O)Aryl; —N(Aryl)C(O)Phenyl; —N(Aryl)C(O)Heteroaryl;—N(Phenyl)C(O)CH₃; —N(Phenyl)C(O)C₂₋₆alkyl;—N(Phenyl)C(O)C₃₋₆cycloalkyl; —N(Phenyl)C(O)Aryl; —N(Phenyl)C(O)Phenyl;—N(Phenyl)C(O)Heteroaryl; —N(Heteroaryl)C(O)CH₃;—N(Heteroaryl)C(O)C₂₋₆alkyl; —N(Heteroaryl)C(O)C₃₋₆cycloalkyl;—N(Heteroaryl)C(O)Aryl; —N(Heteroaryl)C(O)Phenyl;—N(Heteroaryl)C(O)Heteroaryl; guanidyl; amidinyl; —SO₂NH₂; —OCHF₂; —CF₃;—OCF₃; and such moieties may also be optionally substituted by afused-ring structure or bridge, for example —OCH₂O— or—O—C_(1- or 2-6)alkylene-O—. These substituents may optionally befurther substituted with a substituent selected from such groups.

Preferably, when the structural moiety of formula (I) has the structuredepicted in formula (III 3e), the ring corresponding to the A-ring offormula (I) (in this case the pyrrole ring) may be optionallysubstituted, and when the pyrrole ring is substituted it is substitutedby one or more substituents independently selected from —CH₃,C_(2to4)alkyl, halogen, —OCH₃, and —OC_(2to4)alkyl.

Therein, R¹ and R² are as defined for formula (I) and R⁴ to R⁸ areindependently selected from the group consisting of H, —CH₃,C_(2to4)alkyl, halogen, hydroxyl, —OCH₃, —OC_(2to4)alkyl, —CF₃, —OCF₃,—NH₂, —CH₂NH₂, —N(CH₃)₂, —NO₂, —CH₂OH, —CO₂CH₃, —CO₂C_(2to4)alkyl,—CO₂H, —N(alkyl)₂ where the two alkyl groups are independently selectedfrom —CH₃ or C_(2to4)alkyl, —NH(alkyl) where the alkyl group is selectedfrom —CH₃ or C_(2to4)alkyl, 4-morpholinyl, 1-piperidinyl,4H-piperazinyl, 4-C_(1to4)alkyl-piperazinyl, and4-C_(3to6)cycloalkyl-piperazinyl.

When R¹ or R² is aryl, phenyl, heteroaryl, or benzyl optionallysubstituted on the phenyl ring, they may be substituted with one or moreof the substituents as described elsewhere herein. Other examples of R¹or R² groups according to the present invention include phenylsubstituted with a substituent selected from the group consisting ofphenyl, substituted phenyl, —CH₂CF₃, —CH₂OCF₃, —CHF₂, piperazinyl,N-Methyl-piperazinyl, N-acyl-piperazinyl for exampleN-acetyl-piperazinyl, N-sulfonyl-piperazinyl for exampleN-methylsulfonyl-piperazinyl or N-phenylsulfonyl-piperazinyl,morpholinyl, —NHCOC_(1- or 2to6)alkyl, —NHCOC_(1- or 2to8)hydrocarbonand —NHCO(CH₂)₄C≡CH, where said substituent is present at the positionof the phenyl ring para to the point of connection of the phenyl ring tothe ring of the compounds of the invention which bears the R¹ and R²groups. Other examples of R¹ or R² groups according to the presentinvention include phenyl substituted with a substituent selected fromthe group consisting of phenyl, substituted phenyl, —CH₂CF₃, —CH₂OCF₃,—CHF₂, piperazinyl, N-Methyl-piperazinyl, N-acyl-piperazinyl for exampleN-acetyl-piperazinyl, N-sulfonyl-piperazinyl for exampleN-methylsulfonyl-piperazinyl or N-phenylsulfonyl-piperazinyl,morpholinyl, —NHCOC_(1- or 2to6)alkyl, —NHCOC_(1- or 2to8)hydrocarbonand —NHCO(CH₂)₄C≡CH, where said substituent is present at the positionof the phenyl ring meta to the point of connection of the phenyl ring tothe ring of the compounds of the invention which bears the R¹ and R²groups. Other examples of R¹ or R² groups according to the presentinvention include phenyl substituted with a substituent selected fromthe group consisting of phenyl, substituted phenyl, —CH₂CF₃, —CH₂OCF₃,—CHF₂, piperazinyl, N-Methyl-piperazinyl, N-acyl-piperazinyl for exampleN-acetyl-piperazinyl, N-sulfonyl-piperazinyl for exampleN-methylsulfonyl-piperazinyl or N-phenylsulfonyl-piperazinyl,morpholinyl, —NHCOC_(1- or 2to6)alkyl, —NHCOC_(1- or 2to8)hydrocarbonand —NHCO(CH₂)₄C≡CH, where said substituent is present at the positionof the phenyl ring ortho to the point of connection of the phenyl ringto the ring of the compounds of the invention which bears the R¹ and R²groups. In each the above examples, the phenyl ring which is substitutedin either the ortho, meta, or para position with the listed substituentsmay be replaced with a heteroaryl ring (for example a pyridyl orpyrimidyl ring) substituted in said ortho, meta or para position withthe listed substituents, a benzyl group whereby the phenyl ring of thebenzyl group is substituted in said ortho, meta or para position withthe listed substituents, or aryl substituted in said ortho, meta or paraposition with the listed substituents.

Preferably in the present invention, when R¹ or R² is heteroaryl it isoptionally substituted 6-membered heteroaryl, for example optionallysubstituted pyridinyl (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, most preferably optionally substituted pyridinyl (pyridyl) orpyrimidinyl. These rings are optionally substituted with one or moresubstituents, suitable substituents being described elsewhere herein, inparticular with one or more substituents corresponding to thosedescribed as being preferred for R¹ or R² in the compounds of formula(I) when R¹ or R² is (optionally) substituted aryl or phenyl.

In one embodiment of the present invention, one of R¹ or R² is —CH₃. Inone embodiment of the present invention, one of R¹ or R² is —H. In oneembodiment of the present invention, one of R¹ or R² is —CH₂N(CH₃)₂. Inone embodiment of the present invention, one of R¹ or R² is halogen,preferably Cl.

In a preferred embodiment of the present invention, the compoundscomprising or consisting of the moieties of the invention are selectedfrom the group consisting of

The proviso that at least one of R¹ or R² in the moieties of formulae(I), (VII) and (VII) possesses 3 or more carbon atoms is non-essentialfor anti-microbial activity. In the case that the compounds of theinvention are directed to use in the treatment of microbial infection,either or both of R¹ or R² may possess less than 3 carbon atoms, forexample both R¹ and R² can be a methyl group.

The present invention is also directed towards processes or methods formaking the compounds of the invention. Accordingly, the processes forthe production of the compounds of the invention and intermediatesthereto as outlined under Methods A to I in the Examples Sectionhereinafter are also included as further aspects of the presentinvention. Any novel intermediates as defined in the Schemes, Lists,Examples or Methods herein are also included within the scope of theinvention.

Other compounds of formula (I) may be prepared by methods analogous tothose described in the Examples section or by methods known per se.Further details for the preparation of the compounds of formula (I) arefound in the Examples.

The compounds of formula (I) may be prepared singly or as compoundlibraries comprising at least 2, for example, 5 to 1,000, compounds andmore preferably 10 to 100 compounds of formula (I). Compound librariesmay be prepared by a combinatorial “split and mix” approach or bymultiple parallel synthesis using either solution or solid phasechemistry, using procedures to those skilled in the art.

During the synthesis of the compounds of formula (I), labile functionalgroups in the intermediate compounds, e.g. hydroxyl, carboxy and aminogroups, may be protected. The protecting groups may be removed at anystage in the synthesis of the compounds of formula (I) or may be presenton the final compound of formula (I). A comprehensive discussion of theways in which various labile functional groups may be protected andmethods for cleaving the resulting derivatives is given in, for example,Protective groups in Organic Chemisty, T. W. Greene and P. G. M Wuts,(1991) Wiley-Interscience, New York, 2^(nd) edition.

The preferred groups for variables recited herein in relation to thecompounds of formula (I) also apply to the intermediate compounds.

The present invention relates to a compound comprising or consisting ofthe structural moiety of formula (I) or a pharmaceutically-acceptablesalt of said compound. In some embodiments, the moiety of formula (I)may be the only moiety comprised in the structure of the compound of theinvention.

While the preferred groups for each variable have generally been listedabove separately for each variable, preferred compounds of thisinvention include those in which several or each variable in formula (I)is selected from the preferred groups for each variable. Therefore, thisinvention is intended to include all combinations of preferred listedgroups.

Representative compounds of the invention which may be mentioned arethose provided in the Examples as the free base or a pharmaceuticallyacceptable salt thereof. The molecular weight of the compounds of theinvention is preferably less than 800 g/mol, more preferably less than600 g/mol.

As used throughout herein, unless stated otherwise, “alkyl” means carbonchains which may be linear (straight chain) or branched. Examples of,for example, C_(2to4)alkyl groups include ethyl, n-propyl, isopropyl,n-, iso-, sec- and tert-butyl. As used throughout herein, unless statedotherwise, “cycloalkyl” means rings of which the atoms forming the ringitself are exclusively carbon atoms. The term “halogen” as usedthroughout herein means, unless otherwise stated, F, Cl, Br or I. Asused herein, the term “halogen” preferably means F, Cl or Br. As usedthroughout herein, the term “heteroaryl” rings means 5- or 6-memberedunsubstituted or substituted N-containing heteroaryl rings containing upto 2 additional heteroatoms independently selected from N, O and S.Examples of such heteroaryl rings are pyrrolyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,indolyl. The term “aryl” as used throughout herein may refer tounsubstituted aryl and/or substituted aryl. Compounds describedthroughout herein may contain one or more asymmetric centers and maythus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The present invention includes all stereoisomers of thecompounds of the invention and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

In an exemplary aspect of the invention, an “aryl” group is preferablyan unsaturated aromatic carbocyclic group of from 6 to 14 carbon atomshaving a single ring (e.g., phenyl) or multiple condensed rings (e.g.,naphthyl or anthryl). Particular aryls include phenyl, biphenyl,naphthyl and the like.

In an exemplary aspect of the invention, a “heteroaryl” or“heteroaromatic” ring/group is preferably an aryl ring system having oneto four heteroatoms (e.g., O, S, N, or combinations thereof) as ringatoms in a heteroaromatic ring system, wherein the remainder of theatoms are carbon atoms. The heteroaryl moiety preferably may consist ofa single or fused ring system. A typical single heteroaryl ring in thissense is a 5- to 6-membered ring containing one to four, preferably oneto three or one to two heteroatoms selected from oxygen, sulfur andnitrogen and a typical fused heteroaryl ring system is a 9- to10-membered ring system containing one to four heteroatoms selected fromoxygen, sulfur and nitrogen. Examples of 5-membered (single ring)heteroaryl include pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl,oxadiazolyl, thiadiazolyl, dithiazolyl, and tetrazolyl. Examples of6-membered (single ring) heteroaryl include pyridyl, pyrazinyl,pyrimidyl, pyridazinyl, triazinyl, and tetrazinyl. Examples of fusedheteroaryl ring systems include indolyl, oxindolyl, indazolyl,coumarinyl, 1H-indolyl, 1H-indazolyl, benzo[d]thiazolyl, benzofuranyl,purinyl, benzimidazolyl, quinolinyl, isoquinolinyl, benzothiophenyl,benzoxazolyl, 1,2-diazanaphthyl, 1,3-diazanaphthyl, 1,4-diazanaphthyl,1,5-diazanaphthyl, 1,6-diazanaphthyl, 1,7-diazanaphthyl,1,8-diazanaphthyl, 2,3-diazanaphthyl, 2,6-diazanaphthyl, and2,7-diazanaphthyl. The heteroaryl group may preferably be attached tothe chemical entity or moiety of the compounds of the invention to whichthey are bonded by any one of the atoms within the aromatic ring system(e.g., imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl,pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrid-5-yl, or pyrid-6-yl). In oneembodiment, the heteroaryl group is a 5- to 10-membered heteroarylgroup.

Examples of 5-membered (single ring) heteroaryl include pyrrolyl (e.g.1-, 2-, 3-, 4-, or 5-pyrrolyl), furanyl (e.g. 2-, 3-, 4-, or 5-furanyl),thienyl (e.g. 2-, 3-, 4-, or 5-thienyl), imidazolyl (e.g. 1-, 2-, 4-, or5-imidazolyl), pyrazolyl (e.g. 1-, 3-, 4-, or 5-pyrazolyl), oxazolyl(e.g. 2-, 4-, or 5-oxazolyl), isoxazolyl (e.g. 3-, 4-, or 5-isoxazolyl),thiazolyl (e.g. 2-, 4-, or 5-thiazolyl), isothiazolyl (e.g. 3-, 4-, or5-isothiazolyl), triazolyl (e.g. 4-, or 5-(1H-1,2,3-triazol)-yl; 4-, or5-(2H-1,2,3-triazol)-yl; 3-, or 5-(1H-1,2,4-triazol)-yl; 3-, or5-(4H-1,2,4-triazol)-yl), furazanyl (e.g. 3-, or 4-furazanyl),oxadiazolyl (e.g. 3-, or 4-(1,2,5-oxadiazol)-yl; 3-, or5-(1,2,4-oxadiazol)-yl; 4-, or 5-(1,2,3-oxadiazol)-yl; 2-, or5-(1,3,4-oxadiazol)-yl), thiadiazolyl (e.g. 3-, or4-(1,2,5-thiadiazol)-yl; 3-, or 5-(1,2,4-thiadiazol)-yl; 4-, or5-(1,2,3-thiadiazol)-yl; 2-, or 5-(1,3,4-thiadiazol)-yl), and tetrazolyl(e.g. 1-, or 5-(1H-tetrazolyl); 1-, or 4-(2H-tetrazolyl).

Examples of 6-membered (single ring) heteroaryl include pyridyl (e.g.2-, 3-, 4-, 5- or 6-pyridyl), pyrazinyl (e.g. 2-, 3-, 5- or6-pyrazinyl), pyrimidyl (e.g. 2-, 4-, 5- or 6-pyrimidyl), pyridazinyl(e.g. 3-, 4-, 5- or 6-pyridazinyl), triazinyl (e.g. 4-, or 5-, or6-(1,2,3-triazin)-yl; 3-, or 5-, or 6-(1,2,4-triazin)-yl; 2-, or 4-, or6-(1,3,5-triazin)-yl).

Examples of bicyclic fused ring heteroaryl include indolyl (e.g. 1-, 2-,3-, 4-, 5-, 6-, or 7-indolyl), benzofuranyl (e.g. 2-, 3-, 4-, 5-, 6-, or7-benzofuranyl), indazolyl (e.g. 1-, 3-, 4-, 5-, 6-, or 7-indazolyl),oxindolyl (e.g. 1-, 3-, 4-, 5-, 6-, or 7-oxindolyl), benzimidazolyl(e.g. 1-, 2-, 4-, 5-, 6-, or 7-benzimidazolyl), benzothiophenyl (e.g.2-, 3-, 4-, 5-, 6-, or 7-benzothiophenyl), benzoxazolyl (e.g. 2-, 4-,5-, 6-, or 7-benzoxazolyl), benzo[d]thiazolyl (e.g. 2-, 4-, 5-, 6-, or7-benzo[d]thiazolyl), quinolinyl (e.g. 2-, 3-, 4-, 5-, 6-, 7-, or8-quinolinyl), isoquinolinyl (e.g. 1-, 3-, 4-, 5-, 6-, 7-, or8-isoquinolinyl), coumarinyl (e.g. 3-, 4-, 5-, 6-, 7-, or 8-coumarinyl),purinyl (e.g. 2-, 6-, 8-, or 9-purinyl), 1,2-diazanaphthyl (e.g. 3-, 4-,5-, 6-, 7-, 8-(1,2-diazanaphth)-yl), 1,3-diazanaphthyl (e.g. 2-, 4-, 5-,6-, 7-, 8-(1,3-diazanaphth)-yl), 1,4-diazanaphthyl (e.g. 2-, 3-, 5-, 6-,7-, 8-(1,4-diazanaphth)-yl), 1,5-diazanaphthyl (e.g. 2-, 3-, 4-, 6-, 7-,8-(1,5-diazanaphth)-yl), 1,6-diazanaphthyl (e.g. 2-, 3-, 4-, 5-, 7-,8-(1,6-diazanaphth)-yl), 1,7-diazanaphthyl (e.g. 2-, 3-, 4-, 5-, 6-,8-(1,7-diazanaphth)-yl), 1,8-diazanaphthyl (e.g. 2-, 3-, 4-, 5-, 6-,7-(1,8-diazanaphth)-yl), 2,3-diazanaphthyl (e.g. 1-, 4-, 5-, 6-, 7-,8-(2,3-diazanaphth)-yl), 2,6-diazanaphthyl (e.g. 1-, 3-, 4-, 5-, 7-,8-(2,6-diazanaphth)-yl), and 2,7-diazanaphthyl (e.g. 1-, 3-, 4-, 5-, 6-,8-(2,7-diazanaphth)-yl). More preferably when B is bicyclic fused ringheteroaryl, it is selected from the group consisting of indolyl (e.g.1-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl), benzofuranyl (e.g. 2-, 3-, 4-,5-, 6-, or 7-benzofuranyl), indazolyl (e.g. 1-, 3-, 4-, 5-, 6-, or7-indazolyl), and oxindolyl (e.g. 1-, 3-, 4-, 5-, 6-, or 7-oxindolyl).

In an exemplary aspect of the invention, C₃₋₆cycloalkyl may be selectedfrom cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In oneexemplary aspect of the invention, C₃₋₆cycloalkyl may be selected fromcyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, whereby thecycloalkyl ring is a substituent on an atom and is attached to said atomby a single covalent bond. In one exemplary aspect of the invention,C₃₋₆cycloalkyl may be selected from cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl, whereby the cycloalkyl ring is asubstituent on an atom and is attached to said atom by a double covalentbond. In one exemplary aspect of the invention, C₃₋₆cycloalykl may beselected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl,whereby the cycloalkyl ring is a substituent on an atom and constitutesa spiro substituent on said atom, i.e. two atoms of the cycloalkyl ringare directly and independently bonded to said atom.

When a tautomer of the compound of the invention exists, the presentinvention includes any possible tautomers and pharmaceuticallyacceptable salts thereof, and mixtures thereof, except wherespecifically drawn or stated otherwise.

When the compound of the invention and pharmaceutically acceptable saltsthereof exist in the form of solvates or polymorphic forms, the presentinvention includes any possible solvates and polymorphic forms. A typeof a solvent that forms the solvate is not particularly limited so longas the solvent is pharmacologically acceptable. For example, water,ethanol, propanol, acetone or the like can be used.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (bothcupric and cuprous), ferric, ferrous, lithium, magnesium, potassium,sodium, zinc and the like salts. Particularly preferred are theammonium, calcium, magnesium, potassium and sodium salts. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, as well as cyclic amines andsubstituted amines such as naturally occurring and synthesizedsubstituted amines. Other pharmaceutically acceptable organic non-toxicbases from which salts can be formed include arginine, betaine,caffeine, choline, N′,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the invention is basic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicacids, including inorganic and organic acids. Such acids include, forexample, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Since the compounds of theinvention are intended for pharmaceutical use they are preferablyprovided in substantially pure form, for example at least 60% pure, moresuitably at least 75% pure, especially at least 98% pure (% are on aweight for weight basis).

The invention also provides a compound comprising the moiety of theinvention, or a pharmaceutically acceptable salt thereof, for use as apharmaceutical. The invention also provides a pharmaceutical compositioncomprising a compound comprising the moiety of the invention, incombination with a pharmaceutically acceptable carrier.

Preferably the composition is comprised of a pharmaceutically acceptablecarrier and a non-toxic therapeutically effective amount of a compoundof the invention, or a pharmaceutically acceptable salt thereof.

Moreover, the invention also provides a pharmaceutical composition foruse in the treatment of disease by modulating microbial activity,resulting in the prophylactic or therapeutic treatment of microbialinfection, comprising a pharmaceutically acceptable carrier and anon-toxic therapeutically effective amount of compound comprising themoiety of the invention, or a pharmaceutically acceptable salt thereof.

The pharmaceutical compositions may optionally comprise othertherapeutic ingredients or adjuvants. The compositions includecompositions suitable for oral, rectal, topical, and parenteral(including subcutaneous, intramuscular, and intravenous) administration,although the most suitable route in any given case will depend on theparticular host, and nature and severity of the conditions for which theactive ingredient is being administered. The pharmaceutical compositionsmay be conveniently presented in unit dosage form and prepared by any ofthe methods well known in the art of pharmacy.

In practice, the compounds of the invention, or pharmaceuticallyacceptable salts thereof, can be combined as the active ingredient inintimate admixture with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending on the form of preparation desired foradministration, e.g. oral or parenteral (including intravenous).

Thus, the pharmaceutical compositions can be presented as discrete unitssuitable for oral administration such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient.Further, the compositions can be presented as a powder, as granules, asa solution, as a suspension in an aqueous liquid, as a non-aqueousliquid, as an oil-in-water emulsion, or as a water-in-oil liquidemulsion. In addition to the common dosage forms set out above, thecompound of the invention, or a pharmaceutically acceptable saltthereof, may also be administered by controlled release means and/ordelivery devices. The compositions may be prepared by any of the methodsof pharmacy. In general, such methods include a step of bringing intoassociation the active ingredient with the carrier that constitutes oneor more necessary ingredients. In general, the compositions are preparedby uniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation. The compounds ofthe invention, or pharmaceutically acceptable salts thereof, can also beincluded in pharmaceutical compositions in combination with one or moreother therapeutically active compounds. The pharmaceutical carrieremployed can be, for example, a solid, liquid, or gas. Examples of solidcarriers include lactose, terra alba, sucrose, talc, gelatin, agar,pectin, acacia, magnesium stearate, and stearic acid. Examples of liquidcarriers are sugar syrup, peanut oil, olive oil, and water. Examples ofgaseous carriers include carbon dioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents, and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.05 mg to about 5 g of the activeingredient and each cachet or capsule preferably containing from about0.05 mg to about 5 g of the active ingredient. For example, aformulation intended for the oral administration to humans may containfrom about 0.5 mg to about 5 g of active agent, compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95 percent of the total composition. Unit dosageforms will generally contain between from about 1 mg to about 2 g of theactive ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof. Pharmaceuticalcompositions of the present invention can be in a form suitable fortopical use such as, for example, an aerosol, cream, ointment, lotion,dusting powder, or the like. Further, the compositions can be in a formsuitable for use in transdermal devices. These formulations may beprepared, using a compound of the invention, or a pharmaceuticallyacceptable salt thereof, via conventional processing methods. As anexample, a cream or ointment is prepared by admixing hydrophilicmaterial and water, together with about 5 wt % to about 10 wt % of thecompound, to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, or pharmaceutically acceptablesalts thereof, may also be prepared in powder or liquid concentrateform. Generally, dosage levels on the order of 0.01 mg/kg to about 150mg/kg of body weight per day are useful in the treatment of theabove-indicated conditions, or alternatively about 0.5 mg to about 7 gper patient per day. For example, microbial infection may be effectivelytreated by the administration of from about 0.01 to 50 mg of thecompound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5 g per patient per day. It is understood, however, thatthe specific dose level for any particular patient will depend upon avariety of factors including the age, body weight, general health, sex,diet, time of administration, route of administration, rate ofexcretion, drug combination and the severity of the particular diseaseundergoing therapy.

The invention also provides a compound of the invention, or apharmaceutically acceptable salt thereof, for treating a medicalcondition, in particular for treating microbial infection and/orinfectious diseases. Examples of medical conditions or diseases whichmay be treated by the compounds or pharmaceutical compositions of theinvention include respiratory tract infections, complicated skin andsoft tissue infections, complicated intra-abdominal infections,community acquired pneumonia, hospital-acquired pneumonia,ventilator-associated pneumonia, urinary tract infections, bacterialmeningitis, infective endocarditis, sepsis, osteomyelitis, septicarthritis, septicemia, anthrax, osteomyelitis, tuberculosis, leprosy,necrotizing fasciitis, scarlet fever, rheumatic fever, postpartum fever,and streptococcal toxic shock syndrome, and additional nosocomialinfections, for example infections caused from the use of intravascularcatheters.

The invention also provides a method for the treatment of a disease orcondition in which microbes play a role, said method comprising a stepof administering to a subject in need thereof an effective amount of acompound of the invention, said subject being a mammal, in particular ahuman.

The invention also provides a method for the treatment of microbialinfection, said method comprising a step of administering to a subjectin need thereof an effective amount of a compound of the invention, saidsubject being a mammal, in particular a human.

The compounds of the invention may show activity against, and thus beused in the treatment of microbial infections caused by gram-positivebacteria or gram-negative bacteria. The compounds of the invention arepreferably used in the treatment of microbial infections caused bygram-positive bacteria, in particular by one or more gram-positivebacterial species selected from the list consisting of Streptococci,Staphylococci, Bacilli, Enterococci and Mycobacteria. In someembodiments, the compounds of the invention are used in the treatment ofmicrobial infections caused by Streptococcus pneumoniae. In someembodiments, the compounds of the invention are used in the treatment ofmicrobial infections caused by Staphylococcus aureus. In someembodiments, the compounds of the invention are used in the treatment ofmicrobial infections caused by methicillin-resistant Staphylococcusaureus. In some embodiments, the compounds of the invention are used inthe treatment of microbial infections caused by Staphylococcusepidermidis. In some embodiments, the compounds of the invention areused in the treatment of microbial infections caused by Bacilli asexemplified by the activity against Bacillus subtilis. In someembodiments, the compounds of the invention are used in the treatment ofmicrobial infections caused by Enterococcus faecium. In someembodiments, the compounds of the invention are used in the treatment ofmicrobial infections caused by Enterococcus faecalis. In someembodiments, the compounds of the invention are used in the treatment ofmicrobial infections caused by Mycobacteria as exemplified in theactivity against Mycobacterium smegmatis. In some embodiments, thecompounds of the invention are used in the treatment of microbialinfections caused by one or more of these organisms.

The compounds of the present invention are preferably used in thetreatment of microbial diseases caused by bacteria which exhibitresistance to existing antibiotics, in particular Staphylococci,Streptococci and Enterococci which exhibit resistance to one or moreantibiotics. Preferred compounds of the invention exhibit activityagainst, and may thus be used in the treatment of microbial infectionscaused by, methicillin-resistant Staphylococcus aureus, still morepreferably against methicillin-resistant Staphylococcus aureus whichshow resistance to other antibiotics, for example to other beta-lactamantibiotics, to macrolide antibiotics, to quinolones, or tocephalosporins, or to so-called antibiotics of“last resort” e.g.daptomycin, vancomycin, or linezolid, as well as to novel antibacterialagents such as moenomycin and platensimycin. It has been found that thecompounds of the invention may be at least tenfold more potent againstmethicillin-resistant Staphylococcus aureus which is also resistant todaptomycin (daptomycin-resistant MRSA) than against daptomycin-sensitivestrains. The compounds of the invention may thus exhibit advantageousproperties for the treatment of infections caused by or caused at leastin part by staphylococci resistant to daptomycin. Preferred compounds ofthe invention exhibit activity against, and may thus be used in thetreatment of microbial infections caused by penicillin-resistantStreptococcus pneumoniae or erythromycin-resistant Streptococcuspneumoniae or tetracycline-resistant Streptococcus pneumoniae orpenicillin-, erythromycin-, and tetracycline-resistant Streptococcuspneumoniae. The compounds of the invention may thus be used asantibiotics.

Generally, the compounds of the invention, in particular the preferredcompounds of the invention, exhibit a therapeutic window foranti-microbial activity over toxicity to healthy human cells.

The invention also provides the use of a compound of the invention, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a condition as defined above. In themethods of the invention the term “treatment” includes both therapeuticand prophylactic treatment.

The compounds of the invention may exhibit advantageous propertiescompared to known compounds or combination therapies for the treatmentof microbial infection. The compounds of the invention, orpharmaceutically acceptable salts thereof, may be administered alone orin combination with one or more other therapeutically active compounds.The other therapeutically active compounds may be for the treatment ofthe same disease or condition as the compounds of the invention or adifferent disease or condition, for example in their use inimmunocompromised patients. In a preferred embodiment the treatmentconsists of combining a compound of the invention with platensimycin.The therapeutically active compounds may be administered simultaneously,sequentially or separately.

The compounds of the invention may be administered with other activecompounds for the treatment of microbial infection, for example togetherwith penicillins, cephalosporins, polymyxins, rifamycins, quinolones,sulfonamides, macrolide antibiotics, lincosamides, tetracyclines,aminoglycosides, cyclic lipopeptides (such as daptomycin),glycylcyclines, oxazolidinones (such as linezolid). Inhibitors ofbacterial efflux pumps, such as the AcrAB-TolC pump or the CmeABC effluxpump, may also be administered simultaneously, sequentially orseparately with the compounds of the invention.

Combination therapy comprising the administration of a compound of theinvention, or a pharmaceutically acceptable salt thereof, and at leastone other agent, for example another agent for the treatment ofmicrobial infection, represents a further aspect of the invention.

The present invention also provides a method for the treatment ofmicrobial infection in a mammal, such as a human, which method comprisesadministering an effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof, and another agent, for exampleanother agent for the treatment of microbial infection, to a mammal inneed thereof.

The invention also provides the use of a compound of the invention, or apharmaceutically acceptable salt thereof, and another agent for thetreatment of microbial infection.

The invention also provides the use of a compound of the invention, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in combination with another agent, for the treatmentof microbial infection.

The compound of the invention, or a pharmaceutically acceptable saltthereof, and the other agent(s) may be co-administered or administeredsequentially or separately.

Co-administration includes administration of a formulation whichincludes both the compound of the invention, or a pharmaceuticallyacceptable salt thereof, and the other agent(s), or the simultaneous orseparate administration of different formulations of each agent. Wherethe pharmacological profiles of the compound of the invention, or apharmaceutically acceptable salt thereof, and the other agent(s) allowit, co-administration of the two agents may be preferred. The inventionalso provides the use of a compound of the invention, or apharmaceutically acceptable salt thereof, and another agent in themanufacture of a medicament for the treatment of microbial infection.

The invention also provides a pharmaceutical composition comprising acompound of the invention, or a pharmaceutically acceptable saltthereof, and another anti-microbial agent, and a pharmaceuticallyacceptable carrier.

When described herein that the compounds of the invention may be used inthe treatment of microbial infection, it is to be understood that theymay also be used in the treatment of a disorder, affliction or illnesscaused at least in part by microbial infection. As used hereinthroughout, the term “microbial infection” is to be understood topreferably mean “bacterial infection.

The invention also encompasses the use of such compositions in themethods described above.

The antibacterial activity of compounds of the invention againstmethicillin-resistant Staphylococcus aureus (MRSA) can be amplified byinterfering with bacterial lipid biosynthesis.

Thus, synergistic activity with platensimycin, an inhibitor of bacteriallipid biosynthesis, is observed for compounds of the invention. Thissynergistic activity is determined from the fractional inhibitoryconcentration (FIC) indexes (FICi). An FIC is obtained by dividing theMIC of the compound when used in combination by the MIC when used alone,i.e. when using compounds A and B in combinationFIC_(A)=MIC_(A in combination)/MIC_(A alone) andFIC_(B)=MIC_(B in combination)/MIC_(B alone). FICi is the sum of the twoFIC values for each compound; that is, FICi=FIC_(A)+FIC_(B). If theFICi≤0.5, then the interaction of the two compounds is defined as asynergistic interaction. Particularly preferred compounds of theinvention for achieving synergistic activity againstmethicillin-resistant Staphylococcus aureus (MRSA) through their use incombination with platensimycin are compounds 2, 6, 19, 25, 26, 48, 50,43, 44, 49, 64, 65, and 68, most preferably compounds 2, 6, 19, 25, 26,48, and 50.

This same phenomenon is also observed in cells in which bacterial lipidbiosynthesis is impacted, for example, by their being at least partiallyresistant to daptomycin. Here, the compounds of the invention may be atleast tenfold more potent against MRSA strains in which bacterial lipidbiosynthesis is impacted by their resistance to daptomycin than againstthe parental MRSA strain without daptomycin resistance. In this respect,compounds 2, 6, 19, 25, 26, 48, 50, 43, 44, 49, 64, 65, and 68 areparticularly preferred.

Accordingly, in a preferred embodiment at least one compound of theinvention is combined with at least one inhibitor of bacterial lipidsynthesis, preferably with at least platensimycin. In a preferredembodiment the compounds of the invention are used in treatments whichconsist of combining the activity of a compound of the invention withthe activity of platensimycin. This combination may be achieved throughthe dosing each of these compounds (compound of the invention and atleast one inhibitor of bacterial lipid synthesis) separately or bydosing them together in a single dosage form. The compounds may beco-administered, administered sequentially or administered entirelyseparately. The combination dosed in any of these manners may be used inthe treatment of microbial infection and/or a disorder, affliction orillness caused at least in part by microbial infection, in particularwhere said microbial infection is a bacterial infection, in particular abacterial infection caused at least in part by methicillin-resistantStaphylococcus aureus.

In a preferred embodiment, the compounds of the invention may be used inthe treatment of microbial infection and/or a disorder, affliction orillness caused at least in part by microbial infection, said microbialinfection being a bacterial infection caused at least in part bybacteria in which bacterial lipid synthesis is negatively impacted, inparticular daptomycin-resistant methicillin-resistant Staphylococcusaureus.

In a preferred embodiment, the compounds of the invention may be used inthe treatment of microbial infection and/or a disorder, affliction orillness caused at least in part by microbial infection, in particularwhere said microbial infection is a bacterial infection, in particular abacterial infection caused at least in part by daptomycin-resistantMRSA. Preferred compounds are compounds 2, 6, 19, 25, 26, 48, 50, 43,44, 49, 64, 65, and 68 or combinations thereof, with compounds 2, 6, 19,25, 26, 48, and 50 or combinations thereof being most preferred.

The compounds of the invention may be used in the treatment of microbialinfection and/or a disorder, affliction or illness caused by or at leastin part by microbial infection, said microbial infection being abacterial infection caused by or at least in part by bacteria in whichbacterial lipid synthesis is negatively impacted, in particulardaptomycin-resistant methicillin-resistant Staphylococcus aureus.Preferred compounds are compounds 2, 6, 19, 25, 26, 48, 50, 43, 44, 49,64, 65, and 68 or combinations thereof, with compounds 2, 6, 19, 25, 26,48, and 50 or combinations thereof being most preferred.

A preferred embodiment relates to a combination of at least one compoundof the invention and at least one inhibitor of bacterial lipidbiosynthesis, in particular platensimycin, for use in the treatment ofmicrobial infection and/or a disorder, affliction or illness caused byor at least in part by microbial infection, in particular where saidmicrobial infection is a bacterial infection, in particular a bacterialinfection caused by or at least in part by methicillin-resistantStaphylococcus aureus. Preferred compounds of the invention arecompounds 2, 6, 19, 25, 26, 48, 50, 43, 44, 49, 64, 65, and 68 orcombinations thereof, with compounds 2, 6, 19, 25, 26, 48, and 50 orcombinations thereof being most preferred. In a further aspect, thecombination of at least one compound of the invention and at least oneinhibitor of bacterial lipid biosynthesis, in particular platensimycin,is provided by combining the two active agents in a single formulationbefore dosing or by dosing the two active agents separately.Accordingly, the present invention also relates to a compositioncomprising (i) at least one compound according to the invention, inparticular at least one compound selected from compounds 2, 6, 19, 25,26, 48, 43, 44, 49, 50, 64, 65 and 68, preferably at least one compoundselected from compounds 2, 6, 19, 25, 26, 48 and 50, and (ii) at leastone inhibitor of bacterial lipid biosynthesis, in particularplatensimycin.

In a preferred embodiment, the compounds of the invention may be used inthe treatment of daptomycin-resistant MRSA.

In another preferred embodiment of the invention, the infection may becaused by or at least in part caused by staphylococci resistant todaptomycin, in particular by daptomycin-resistant MRSA

A further aspect of the present invention relates to a kit comprising afirst composition and a second composition, said first compositioncomprising at least one compound of the invention and said secondcomposition comprising at least one inhibitor of bacterial lipidbiosynthesis, in particular platensimycin, wherein said first and secondcompositions are physically separate from each other.

All publications, including, but not limited to, patents and patentapplication cited in this specification, are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as fullyset forth. The invention will now be described by reference to thefollowing examples which are for illustrative purposes and are not to beconstrued as a limitation of the scope of the present invention.

All measurements and determinations have been carried out at roomtemperature (20° C.) unless otherwise stated.

EXAMPLES

Materials and Methods

Column chromatography was carried out on commercially available silicagel (loose or pre-packed cartridges) unless otherwise stated.

NMR data were obtained in the specified solvent and using the followingmachines:

NMR data for compounds synthesised using synthetic Methods A or B wereobtained using a Brucker 400 MHz Ultrashield spectrometer. NMR data forcompounds synthesised using synthetic Method C were obtained using aBruker AVANCE III HD Spectrometer. NMR data for compounds synthesisedusing synthetic Methods D or E were obtained using a Bruker Avance III600 NMR spectrometer or Bruker Avance DPX300 NMR spectrometer. NMR datafor compounds synthesised using synthetic Methods F to I were obtainedusing a Varian INOVA Plus (400 MHz) spectrometer or Bruker Avance (500MHz) spectrometer.

LCMS data were obtained and HPLC analysis carried out using one or moreof the following methods:

LCMS Procedure #1:

Mobile phases: 10 mM ammonium formate in 9:1 (v/v) water:methanol at pH8 (A) & 10 mM ammonium formate in methanol (B). Chromatography uses aVariant Pursuit C18 column (2.0×20.0 mm, 5 μm, flow rate=0.8 ml/min).Total run time: 5 min.

Gradient Elution:

Time (min) A(%, v/v) B(%, v/v) 0 100 0 0.2 100 0 2.7 0 100 4.4 0 100 5100 0

The system used was the Waters 2795/Micromass Platform. UV detection wasat 180 to 500 nm (diode array detection). The mass spectra were obtainedusing an electrospray ionization source in the positive (ES<+>) mode.

For clarity, in the above table for LCMS procedure #1 in which thedetails of the gradient elution are outlined, the presented data shouldbe understood to mean the following: Between 0 min and 0.2 min 100% ofeluent A was employed. From 0.2 to 2.7 min the eluent mixture wasgradually changed (gradient) such that at 2.7 min an eluent compositionof 100% eluent B was reached. Between 2.7 min and 4.4 min the eluentcomposition was held at 100% eluent B. From 4.4 to 5.0 min the eluentmixture was gradually changed such that at 5.0 min an eluent compositionof 100% eluent A was reached. In all other LCMS and HPLC proceduresdescribed herein in which ‘gradient elution’ is employed, theinformation provided in the respective tables corresponding to the‘gradient elution’ table of LCMS procedure #1 should beinterpreted/understood analogously.

LCMS Procedure #2:

Solvents: acetonitrile (Far UV grade) with 0.1% (v/v) formic acid andwater (high purity via PureLab Option unit) with 0.1% formic acid.Column: Phenomenex Luna 5 μm, C18, 100×4.6 mm (plus guard cartridge).Flow rate: 2 ml/min. Total run time: 6 min.

Mobile phases: water/formic acid (A) & acetonitrile/formic acid (B);gradient elution:

Time (min) A(%, v/v) B(%, v/v) 0.00 95 5 3.50 5 95 5.50 5 95 5.60 95 56.50 95 5

UV detection was via HP or Waters DAD. Start range 210 nm, end range 400nm; range interval 4.0 nm. Other wavelength traces extracted from theDAD data. Optional ELS detection was done using Polymer Labs ELS-1000.

The mass spectra were obtained using an ESCI (combined electrospray/APCIionization source) in ES+, ES−, APCI+ & APCI− modes.

LCMS Procedure #3:

Solvents: acetonitrile (Far UV grade), and water (high purity viaPureLab Option unit) with 10 mM ammonium bicarbonate (ammonium hydrogencarbonate). Column: Waters Xterra-MS 5 μm, C18, 100×4.6 mm. Flow rate: 2ml/min. Total run time: 6 min.

Mobile phases: water/bicarbonate (A) & acetonitrile (B); gradientelution:

Time (min) A(%, v/v) B(%, v/v) 0.00 95 5 0.50 95 5 4.00 5 95 5.50 5 955.60 95 5 6.50 95 5

UV detection was done via HP or Waters DAD. Start range 210 nm, endrange 400 (nm); range interval 4.0 nm. Other wavelength traces extractedfrom the DAD data. Optional ELS detection was done using Polymer LabsELS-1000.

The mass spectra were obtained using an ESCI (combined electrospray/APCIionization source) in ES+, ES−, APCI+ & APCI− modes.

HPLC Procedure #4:

Solvents: Acetonitrile (Far UV grade) with 0.1% (v/v) formic acid andwater (high purity via PureLab Ultra unit) with 0.1% (v/v) formic acid.Column: Supelco, Ascentis® Express C18 or Hichrom Halo C18, 2.7 m C18,150×4.6 mm. Flow rate: 1 ml/min. Total run time: 16 min.

Mobile phases: water/formic acid (A) & acetonitrile/formic acid (B);gradient elution:

Time (min) A(%, v/v) B(%, v/v) 0.00 96 4 3.00 96 4 9.00 0 100 13.6 0 10013.7 96 4 15 96 4

Instrument: Agilent 1100, Binary Pump, Agilent Sampler and Agilent DADdetector. Diode array detection: (300 nm, band width 200 nm; Ref. 450nm, band width 100 nm).

HPLC Procedure #5:

Solvents: as for HPLC procedure #4, Column: Hichrom ACE 3 μm C18-ARmixed mode column 100×4.6 mm. Flow rate: 1 ml/min. Total run time: 20min.

Mobile phases: water/formic acid (A) & acetonitrile/formic acid (B);gradient elution:

Time (min) A(%, v/v) B(%, v/v) 0.00 98 2 3.00 98 2 12.00 0 100 15.4 0100 15.5 98 2 17 98 2

Instrument and detection were as for HPLC procedure #4.

HPLC Procedure #6:

Solvents: 100% Acetonitrile (Far UV grade), and water (High purity viaPureLab Ultra unit) with 10 mM ammonium bicarbonate. Column: Hichrom,ACE Excel 3 μm SuperC18, 150×4.6 mm. Flow rate: 1 ml/min. Total runtime: 16 min.

Mobile phases: 10 mM ammonium bicarbonate in water (A) & 100%acetonitrile (B); gradient elution:

Time (min) A(%, v/v) B(%, v/v) 0.00 95.5 4.5 3.00 95.5 4.4 9.00 0 10013.6 0 100 13.7 95.5 4.5 15 95.5 4.5

Instrument and detection were as for HPLC procedure #4.

LCMS Procedure #7:

Solvents were acetonitrile (Far UV grade) with 0.1% (v/v) formic acid(A) and water (high purity via PureLab Option unit) with 0.1% formicacid (B). The column was a Supelco Ascentis Express C18-2.7 μm column of4.6×30 mm, used at a flow rate of 3 ml/min. Gradient elution was asfollows (% are v/v): 0 min—100% B, 0% A; 0.01 min—100% B, 0% A; 1.5min—0% B, 100% A; 2.2 min—0% B, 100% A; 2.21 min—100% B, 0% A.

UV detection was done via Shimadzu VP HPLC systems with diode arrayUV-VIS detector. Start range 210 nm, end range 400 (nm); range interval4.0 nm. The mass spectra were obtained using electrospray ionization(ESI) in either the ES or ES-mode; scan range was m/z 80-1000.

LCMS Procedure #8:

Mobile phases were acetonitrile with 0.1% (v/v) formic acid (A) andwater with 0.1% formic acid (B). The column was Waters SunFire C18, 3.5μm, 2.1×50 mm. Flow rate: 0.5 ml/min. Total run time: 22 min.

Gradient Elution:

Time (min) A(%, v/v) B(%, v/v) 0.00 95.0 5.0 3.00 95.0 5.0 17.50 5.095.0 19.00 5.0 95.0 19.50 95.0 5.0 20.00 95.0 5.0

UV detection was done via HP or Waters DAD. Start range 210 nm, endrange 400 (nm); range interval 4.0 nm. The mass spectra were obtainedusing an ESCI (combined electrospray/APCI ionization source) in ES+ andES− modes.

LCMS Procedure #9:

Mobile phases were as for procedure #8. The column was Acquity UPLC BEHC18 (50 mm×2.1 mm, 1.7 μm packing diameter). Total run time: 13 min.

Gradient Elution:

Time (min) Flow Rate (ml/min) % (v/v)A %(v/v)B 0 0.9 95 5 1.50 0.9 95 58.75 0.9 20 80 9.50 0.9 10 90 9.80 0.9 10 90 12.00 0.05 95 5

The UV detection was a summed signal from wavelength of 210 nm to 350nm. The mass spectra were obtained using alternate—scan positive andnegative Electrospray (ES+/ES−).

Preparative HPLC Procedure #10:

Mobile phases were a mixture of water: methanol 9:1 (v/v) containing0.1% (v/v) NH₃ (A) and methanol with 0.1% (v/v) NH₃ (B). The column wasan Interchim Puriflash C18 HP 30 μm, 6 g column. Flow rate: 7 ml/min.Total run time: 25 min.

Gradient Elution:

Time (min) % A % B 0 100 0 3 100 0 10 0 100 25 0 100

UV detection was done at 385 nm

Preparative HPLC Procedure #11:

Compounds were purified via reverse phase HPLC using a Gilsonpreparative HPLC system (322 pump; 156 UV/VIS detector; GX281 liquidhandler). The GX281 liquid handler acted as both auto-sampler andfraction collector. The column is either a Waters Sunfire OBD column (10μm; 19×150 mm) for acidic conditions or a Waters Xbridge OBD column (5μm; 19×100 mm) for basic conditions. The gradient used is 95% water & 5%acetonitrile for 1 min to 5% water & 95% acetonitrile over 5 min, thenheld at 5% water & 95% acetonitrile for 4 min. The solvent mixture isthen returned to the initial conditions over 3 min. For elution underacidic conditions, the solvents contain 0.1% (v/v) formic acid, whilstfor elution under obtain basic conditions the solvents contain 10 mMammonium bicarbonate. A flow rate of 20 ml/min is used. To decide whichconditions are best, compounds are screened analytically prior topurification, whereby each sample is run under both acidic and basicconditions (0.5 μl injection, 5/95 gradient for 5 minutes). Thepurification is controlled by Trilution® software through monitoring at260 nm and 230 nm. Collected fractions are analyzed by UPLC (WatersAcquity with SQD mass spectrometer). The fractions containing thedesired product are concentrated and lyophilized by vacuumcentrifugation (Genevac) or lyophilized separately using a Virtisfreeze-drier.

Where necessary, the standard gradient may be amended for challengingseparations.

Preparative HPLC Procedure #12:

Mobile phases were 10 mM ammonium bicarbonate adjusted to pH=10 withammonia (A) and acetonitrile (B). The column was an Xbridge Prep. MS C18OBD column (5 μm; 150×30 mm). The following gradient was used:

Time (min) % A % B (v/v) 0 97 3 1 97 3 30 0 100 35 0 100

The flow rate was 50 ml/min; stop-time was 35 min. UV detection was asummed signal from a wavelength of 210 to 600 nm.

Abbreviations and Acronyms

-   AcOH: Acetic acid;-   AcOEt: Ethyl acetate;-   ADDP: Azodicarboxylic dipiperidine;-   APCI: Atmospheric Pressure Chemical Ionization;-   BA: Butylamine;-   CDI: 1,1′-Carbonyldiimidazole;-   CH₂Cl₂: Dichloromethane;-   CHCl₃: Chloroform;-   CsF: Cesium fluoride;-   DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene;-   DCM: Dichloromethane;-   DEA: Diethylamine;-   DIPE: Diisopropyl ether;-   DIPEA: N,N-Diisopropylethylamine-   DMAP: Dimethylpyridin-4-ylamine;-   DME: Dimethoxyethane;-   DMF: Dimethylformamide;-   DMSO: Dimethyl sulfoxide;-   EDCI: (3-Dimethylaminopropyl)ethylcarbodiimide hydrochloride;-   ESCI: Multi-Mode Ionization Source combining high-speed switching    between electrospray ionization (ESI) and Atmospheric Pressure    Chemical Ionization (APCI);-   Et₂O: Diethyl ether;-   Et₃N: Triethylamine;-   EtOH: Ethanol;-   EtOAc: Ethyl Acetate;-   eq: molar equivalents-   h: hour(s);-   HCHO: formaldehyde;-   HCl: Hydrochloric acid;-   HCO₂H: Formic acid;-   H₂O: Water;-   HOBt: 1-Hydroxybenzotriazole monohydrate;-   HPLC: High performance liquid chromatography;-   IH: Isohexane;-   IMS: Industrial methylated spirit;-   IPA: Isopropyl alcohol;-   KOH: Potassium hydroxide-   K₃PO₄: Tripotassium phosphate;-   LAH: Lithium aluminium hydride;-   LCMS: liquid chromatography plus mass spectrometry;-   M: Molar;-   MDR: multi drug resistant;-   MeCN: Acetonitrile;-   MeOH: Methanol;-   MgSO₄: Magnesium sulfate;-   MIC: Minimal Inhibitory Concentration;-   MIC100: minimal concentration to obtain 100% inhibition of bacterial    growth;-   MIC50: minimal concentration to obtain 50% inhibition of bacterial    growth;-   min: minutes;-   mmol: millimoles;-   μM: micro-molar;-   MRSA: methicillin-resistant Staphylococcus aureus;-   MSSA: methicillin-sensitive Staphylococcus aureus;-   MTBE: Methyl-tert-butyl ether;-   Na₂CO₃: Sodium carbonate;-   NaHCO₃: Sodium hydrogen carbonate;-   NaOH: Sodium hydroxide;-   NaNO₂: sodium nitrite;-   Na₂SO₄: Sodium sulfate;-   NH4Cl: Ammonium chloride;-   NH₄HCO₃: Ammonium bicarbonate;-   NH₄OH: Ammonium hydroxide;-   NMR: nuclear magnetic resonance;-   Pd: Palladium;-   Pd⁰: Any palladium species where palladium is in the ‘zero oxidation    state’;-   Pd(OAc)₂: Palladium(II) acetate;-   Pd(PPh)₃: Palladium tetrakis(triphenylphosphine);-   Pd(dppf)Cl₂•CH₂Cl₂:    [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex    with dichloromethane;-   PPh₃: Triphenylphosphine;-   RT: Retention time;-   r.t.: Room temperature (20° C.);-   sat: saturated;-   SCX: Strong Cation Exchange resin;-   SiO₂: Silica gel;-   SM: starting material;-   THF: Tetrahydrofuran;-   TFA: Trifluoroacetic acid;-   TiCl₃: Titanium (III) chloride;-   TLC: thin layer chromatography;-   TSB: Tryptic soy broth;-   TsOH: p-Toluenesulfonic acid monohydrate;-   UPLC: ultra-high performance liquid chromatography;-   UV: ultraviolet.

General Synthetic Routes

The compounds of the present invention may be made using at least one ofthe following synthetic routes and, in some instances, may besuccessfully synthesized via more than one or using a combination ofmore than one of the following synthetic routes. For each of the Methodslisted below which do not relate to the synthesis of a specific singlecompound but instead to the synthesis of compounds which remain, to someextent, generic, e.g. a generic group such as R¹, R², A, B etc remainsin the structure, the specified absolute and molar quantities,concentrations, reaction temperatures, reaction times and purificationprocedures etc serve to provide an indication of typical reactionconditions/procedures used in the synthesis of compounds of theirrespective generic class. Specific compounds made according to such a‘generic’ Method may have been made on a different scale to thatdescribed for the ‘generic’ Method. In such cases, the relative molarequivalents of starting materials and reagents, reaction concentrationsand temperatures are the same as those described in the ‘generic’Method. In certain cases, such absolute and molar quantities,concentrations, reaction temperatures, reaction times and purificationprocedures etc may be altered for the synthesis of given compounds ofthe class, as would be standard laboratory practice for the skilledperson.

The conditions described for general transformations which are commonto/present within more than one Method may be transferable betweenMethods. For example, if more than one Method contains a description ofthe reaction of an aldehyde with a dicarbonyl compound in the presenceof a source of ammonia such to furnish an imidazole-containing compound,if these respective Methods describe differing conditions for thisgeneral transformation then their respective conditions may also beapplicable to the other Method(s) which also describe(s) this generaltransformation.

All reactions have been carried out at room temperature (20° C.) unlessotherwise stated.

Method A (General Procedure for the Synthesis of the Imidazoles in OneStep):

Compounds of Formula (III) may be made through the reaction of analdehyde of formula (XX) with a dicarbonyl compound of formula (XXI) inthe presence of a source of ammonia preferably under standard conditionssuch as heating in a solvent, for example an alcoholic solvent.

Aldehydes of formula (XX) are generally commercially available (forexample from, inter alia, Sigma-Aldrich (St. Louis, Mo., USA), AlfaAesar (Schiltigheim, France), Acros Organics (Geel, Belgium), KeyOrganics (Camelford, UK), Matrix Scientific (Columbia, S.C., USA),Fluorochem (Hadfield, Derbyshire, UK) and Enamine (Kiev, Ukraine)) but,when they are not commercially available, they may also be made by atleast one of a number of standard methods known to the person skilled inthe art such as, for example, reduction of the corresponding nitrile oracid or ester, reaction of an appropriate organometallic or metallatedspecies with N,N-dimethylformamide, general carbonylation methods knownto the skilled person etc. Aldehydes of formula (XX) may also be made byfurther methods such as, for example, those outlined herein under thecorresponding reaction step in Method D (step 1), in Method H or by anynumber of the steps (as required depending on the available startingmaterial) leading to such aldehydes in Method E herein.

Dicarbonyl compounds of formula (XXI) can either be purchased fromcommercial suppliers (for example, inter alia, Sigma-Aldrich (St. Louis,Mo., USA), Alfa Aesar (Schiltigheim, France), Acros Organics (Geel,Belgium), Key Organics (Camelford, UK), Matrix Scientific (Columbia,S.C., USA), Fluorochem (Hadfield, Derbyshire, UK) and Enamine (Kiev,Ukraine)) or made by at least one of a number of standard methods knownto the person skilled in the art such as, for example, byselenium-dioxide-mediated oxidation of the appropriate substrate asdescribed in Rabjohn, N. Org. React, 1976, 44, 261, or by the methodoutlined herein below under Method F.

An example of the use of Method A in the synthesis of 2-furanylimidazolecompounds of the invention is

To the diketone (XXI) (1 eq) dissolved in methanol (0.1 M) was added asolution of aldehyde (XXII) (1 eq) dissolved in methanol (0.1 M). Eightequivalents of ammonium acetate dissolved in methanol (0.8 M) wereadded. The mixture was stirred at 60° C. for two hours. The solvent wasevaporated and the residue was dissolved in ethyl acetate and washedtwice with Na₂CO₃ 0.1 M, then with water. The organic layer wasevaporated and the compound (III 3a) was purified on C18 with asemi-automated system in a H₂O/MeOH gradient using preparative HPLCProcedure 10 (yield 70 to 90%).

By means of example, compound 23 below was synthesized in 70% yield from1-(4-Fluorophenyl)propane-1,2-dione monohydrate (commercially availablefrom, inter alia, Fluorochem (Hadfield, Derbyshire, UK)) and5-[2-(trifluoromethoxy)phenyl]-2-furaldehyde (commercially availablefrom, inter alia, Fluorochem (Hadfield, Derbyshire, UK)) using 0.1 mmolof the aldehyde SM using the conditions outlined above.

4-(4-Fluoro-phenyl)-5-methyl-2-[5-(2-trifluoromethoxy-phenyl)-furan-2-yl]-1H-imidazole23

¹H NMR (400 MHz, DMSO-d₆): δ 2.49 (3H, s, CH₃), 6.98 (1H, d, J=3.2 Hz,furan), 7.02 (1H, d, J=3.2 Hz, furan), 7.27 (2H, m, F-phenyl), 7.50 (2H,m, OCF₃-phenyl), 7.58 (1H, m, OCF₃-phenyl), 7.73 (2H, m, F-phenyl), 8.21(1H, d, J=8.0 Hz, OCF₃-phenyl); LC-MS procedure 1 (electrospray positiveion mode): m/z 403 (M+H)⁺.

Further compounds of the invention made by the above-outlined procedureare outlined herein below. Reactions were performed using 0.1 mmol ofthe appropriate starting aldehyde:

Compound 18 was synthesized in 66% yield from 1-Phenyl-1,2-propanedione(commercially available from, inter alia, Sigma-Aldrich) and5-[2-(trifluoromethoxy)phenyl]-2-furaldehyde (commercially availablefrom, inter alia, Fluorochem (Hadfield, Derbyshire, UK)).

Compound 5 was synthesized in 73% yield from 1-Phenyl-1,2-propanedione(commercially available from, inter alia, Sigma-Aldrich) and5-(4-Chlorophenyl)furfural (commercially available from, inter alia,Sigma-Aldrich).

Compound 17 was synthesized in 59% yield from 1-Phenyl-1,2-propanedione(commercially available from, inter alia, Sigma-Aldrich) and5-[2-(Trifluoromethyl)phenyl]furfural (commercially available from,inter alia, Sigma-Aldrich).

Compound 63 was synthesized in 53% yield from Phenylglyoxal(commercially available from, inter alia, Sigma-Aldrich) and5-[2-(trifluoromethoxy)phenyl]-2-furaldehyde (commercially availablefrom, inter alia, Fluorochem (Hadfield, Derbyshire, UK)).

Compound 25 was synthesized in 59% yield from1-(4-bromophenyl)-1,2-propanedione (commercially available from, interalia, Chembridge) and 5-[2-(Trifluoromethyl)phenyl]furfural(commercially available from, inter alia, Sigma-Aldrich).

Compound 24 was synthesized in 71% yield from1-(4-Chlorophenyl)propane-1,2-dione (commercially available from, interalia, Fluorochem (Hadfield, Derbyshire, UK)) and5-[2-(trifluoromethoxy)phenyl]-2-furaldehyde (commercially availablefrom, inter alia, Fluorochem (Hadfield, Derbyshire, UK)).

Compound 26 was synthesized in 49% yield from1-(4-Trifluoromethylphenyl)-1,2-propanedione monohydrate (commerciallyavailable from, inter alia, Fluorochem (Hadfield, Derbyshire, UK)) and5-[2-(trifluoromethoxy)phenyl]-2-furaldehyde (commercially availablefrom, inter alia, Fluorochem (Hadfield, Derbyshire, UK)).

Compound 38 was synthesized in 59% yield from1-(4-Fluorophenyl)propane-1,2-dione monohydrate (commercially availablefrom, inter alia, Fluorochem (Hadfield, Derbyshire, UK)) and5-[3-(Trifluoromethyl)phenyl]furfural (commercially available from,inter alia, Sigma-Aldrich).

Compound 4 was synthesized in 85% yield from 1-Phenyl-1,2-propanedione(commercially available from, inter alia, Sigma-Aldrich) and5-(3-Chlorophenyl)furfural (commercially available from, inter alia,Sigma-Aldrich).

Compound 29 was synthesized in 67% yield from1-(4-Bromophenyl)propane-1,2-dione (commercially available from, interalia, Otava Chemicals (Vaughan, Ontario, Canada)) and5-[2-(trifluoromethoxy)phenyl]-2-furaldehyde (commercially availablefrom, inter alia, Acros Organics) using 0.1 mmol of the aldehyde SMusing the conditions outlined above.

Compound 28 was synthesized in 70% yield from1-(4-Ethyl-phenyl)-propane-1,2-dione obtained by oxidation with sodiumnitrite of 1-(4-Ethyl-phenyl)-propan-1-one (commercially available from,inter alia, Enamine) and 5-[2-(trifluoromethyl)phenyl]-2-furaldehyde(commercially available from, inter alia, Sigma Aldrich) using 0.1 mmolof the aldehyde SM using the conditions outlined above.

Compound 40 was synthesized in 88% yield from1-(phenyl)-propane-1,2-dione monohydrate (commercially available from,inter alia, Sigma-Aldrich) and5-[3-(Trifluoromethyl-5-chloro)phenyl]furfural (commercially availablefrom Sigma-Aldrich).

Compound 70 was obtained as follows: 100 mg of the imidazoleintermediate(4-phenyl-2-[5-(2-trifluoromethyl-phenyl)-furan-2-yl]-1H-imidazole 123,synthesized in 52% yield according to the methods detailed above) wasdissolved in 2.5 mL of N,N-Dimethylformamide, and 2.5 mL of water andexcess formaldehyde (500 μL of a 37% solution in water) and KOH (1 g)were added.

The reaction mixture was heated at 80° C. for 1 hour. The solvent wasevaporated and the residue was purified on C18 with a semi-automatedsystem in a H₂O:MeOH gradient using preparative HPLC Procedure 10,affording compound 70, below in 70% yield.

Method B (General Procedure for the Synthesis of the Imidazoles in ThreeSteps):

Step 1:

Compounds of formula (XXIV) or (XXVI) may be made by reacting,respectively, compounds of formula (XXIII) or (XXV) with NaNO₂preferably under standards conditions such as in an ethereal solvent,e.g. tetrahydrofuran, at ambient (room) temperature.

The requisite carbonyl starting materials can generally be purchasedfrom commercial suppliers such as, for example, Matrix Scientific,Columbia, S.C., USA or other suppliers. When these starting materialsare not commercially available they may also be made by at least one ofa number of standard methods known to the person skilled in the art formaking carbonyl compounds such as, for example, reduction of thecorresponding nitrile or acid or ester, reaction of an appropriateorganometallic or metallated species with the appropriate carboxylicacid, ester or Weinreb amide, Friedel-Kraft acylation chemistry, etc.

Step 2:

Compounds of formula (XXVII) or (XXVIII) may be made by reacting,respectively, the compounds formula (XXIV) or (XXVI) from Step 1 with analdehyde of formula (XX) in the presence of a source of ammoniapreferably under standard conditions, for example in an alcoholicsolvent with heating.

Aldehydes of formula (XX) are generally commercially available (forexample from, inter alia, Sigma-Aldrich (St. Louis, Mo., USA), AlfaAesar (Schiltigheim, France), Acros Organics (Geel, Belgium), KeyOrganics (Camelford, UK), Matrix Scientific (Columbia, S.C., USA),Fluorochem (Hadfield, Derbyshire, UK) and Enamine (Kiev, Ukraine)) but,when they are not commercially available, they may also be made by atleast one of a number of standard methods known to the person skilled inthe art such as, for example, reduction of the corresponding nitrile oracid or ester, reaction of an appropriate organometallic or metallatedspecies with N,N-dimethylformamide, general carbonylation methods knownto the skilled person etc. Aldehydes of formula (XX) may also be made byfurther methods such as, for example, those outlined herein under thecorresponding reaction step in Method D (step 1), in Method H or by anynumber of the steps (as required depending on the available startingmaterial) leading to such aldehydes in Method E herein.

Step 3:

Compounds of formula (III) may be respectively generated from compoundsof formula (XXVII) or (XXVIII) preferably through standard reductionconditions such as heating in a solvent, for example a dipolar aproticsolvent such as DMF, in the presence of TiCl₃.

An example of the use of Method B in the synthesis of 2-furanylimidazolecompounds of the invention is:

Step 1: Oxidation of the Ketone to Obtain the Keto-Oxime:

A suspension of the starting ketone (XXIX) (5 mmol) and NaNO₂ (345 mg, 5mmol) in THF (10 mL) was cooled to 0° C. Concentrated HCl (6.5 mL) wasadded to the mixture in such a way that the temperature did not exceed10° C. In order to avoid the evolution of nitrous gases the acid wasadded via a needle that was immersed into the reaction mixture. Afterthe addition the cooling bath was removed, and the suspension turnedslowly yellow. The progress of the reaction was monitored by HPLC andTLC. Water (50 mL) was added to the reaction mixture that was pouredinto a separatory funnel with AcOEt (50 mL).

The organic layer was separated and was washed with a saturated aqueoussolution of NaHCO₃ (50 mL) and with brine (50 mL), dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by filtration over a pad of silica gel using dichloromethane asthe eluent to obtain pure keto-oximes (XXX) (yield 45 to 65%).

Step 2: Synthesis of the Hydroxyimidazole

To the keto-oxime (XXX) (1 eq) dissolved in methanol (0.1 M) was added asolution of aldehyde (XXXI) (1 eq) dissolved in methanol (0.1 M). Eightequivalents of ammonium acetate dissolved in methanol (0.8 M) wereadded. The mixture was stirred at 60° C. for eight hours. The solventwas evaporated and the residue was dissolved in ethyl acetate, andwashed twice with Na₂CO₃ 0.1 M, then with water. The organic layer wasevaporated and the compound (XXXII) was purified on C18 with asemi-automated system in a H₂O/MeOH gradient using preparative HPLCProcedure 10 (yield 55 to 75%).

Step 3: Reduction of the Hydroxyl-Imidazole

The hydroxyl-imidazole (XXXII) (100 mg) was dissolved in 4 mL ofN,N-dimethylformamide and 1 mL of a solution of TiCl₃ 20% in 2 N HCl wasadded. The mixture was heated at 60° C. for two hours. The solvent wasevaporated and the compound (XXXIII) was purified on C18 with asemi-automated system in a H₂O/MeOH gradient using preparative HPLCProcedure 10 (yield 75 to 95%).

Depending on the exact structure of the hydroxyimidazole, 100 mgconstitutes differing molar quantities. Within the scope of thesubject-matter claimed, however, this difference in molar quantities wasinsignificant in respect of this experimental procedure and, for every100 mg of hydroximidazole starting material used, 4 ml ofN,N-dimethylformamide and 1 mL of a solution of TiCl₃ 20% in 2 N HClwere used.

Further compounds of the invention made by the above-outlined procedureare outlined herein below (reaction scale may vary between Examples butthe relative quantities of starting materials and reagents as well asconcentrations were consistent with the above-outlined method):

By means of example, compound 30 below was synthesized in 53% yield over3 steps from 4-(4-Bromophenyl)-2-butanone (commercially available from,inter alia, Matrix Scientific (Columbia, S.C., USA)) and5-[2-(trifluoromethoxy)phenyl]-2-furaldehyde (commercially availablefrom, inter alia, Fluorochem (Hadfield, Derbyshire, UK)) using theconditions outlined above.

Step 1:

Using 4-(4-Bromophenyl)-2-butanone (commercially available from, interalia, Matrix Scientific (Columbia, S.C., USA)) as the starting material.

1-(4-Bromo-phenyl)-butane-2,3-dione 2-oxime 124

¹H NMR (400 MHz, DMSO-d₆): δ 2.33 (3H, s, CH₃), 3.73 (2H, s, CH₂) 7.11(2H, d, J=8.4 Hz, Br-phenyl), 7.44 (2H, d, J=8.4 Hz, Br-phenyl).

Step 2:

Using 5-[2-(trifluoromethoxy)phenyl]-2-furaldehyde (commerciallyavailable from, inter alia, Fluorochem (Hadfield, Derbyshire, UK)) asthe reaction partner.

4-(4-Bromo-benzyl)-5-methyl-2-[5-(2-trifluoromethoxy-phenyl)-furan-2-yl]-imidazol-1-ol125

¹H NMR (400 MHz, DMSO-d₆): δ 2.05 (3H, s, CH₃), 3.79 (2H, s, CH₂), 6.88(1H, d, J=3.2 Hz, furan), 6.99 (1H, d, J=3.2 Hz, furan), 7.13 (2H, d,J=8.0 Hz, Br-phenyl), 7.42 (2H, d, J=8.0 Hz, Br-phenyl), 7.46 (3H, m,OCF₃-phenyl), 8.01 (1H, d, J=6.8 Hz, OCF₃-phenyl); LC-MS procedure 1(electrospray positive ion mode): m/z 476, 478 (M+H)⁺.

Step 3:

4-(4-Bromo-benzyl)-5-methyl-2-[5-(2-trifluoromethoxy-phenyl)-furan-2-yl]-1H-imidazole30

¹H NMR (400 MHz, DMSO-d₆): δ 2.45 (3H, s, CH₃), 3.95 (2H, s, CH₂), 6.99(1H, d, J=3.6 Hz, furan), 7.17 (1H, d, J=3.6 Hz, furan), 7.23 (2H, d,J=8.4 Hz, Br-phenyl), 7.40 (2H, m, OCF₃-phenyl), 7.46 (2H, d, J=8.4 Hz,Br-phenyl), 7.53 (1H, m, OCF₃-phenyl), 8.22 (1H, d, J=8.0 Hz,OCF₃-phenyl); LC-MS procedure 1 (electrospray positive ion mode): m/z477, 479 (M+H)⁺.

Method C (General Procedure for the Synthesis of the Imidazoles in TwoSteps):

Step 1:

-   -   where Z is selected from the group consisting of Cl, Br, I and        triflate

Compounds of formula (XXXV) can be made through reaction of aldehydes offormula (XXXIV) with dicarbonyl compounds of formula (XXI) in thepresence of a source of ammonia preferably under standard conditionssuch as heating in a solvent, for example an alcoholic solvent.Aldehydes of formula (XXXIV) can generally be purchased from commercialsuppliers (e.g. Sigma-Aldrich, Apollo Scientific, CombiBlocks (SanDiego, USA) etc) but, in instances where aldehydes of formula (XXXIV)are not commercially available, they may also be made by at least one ofa number of standard methods known to the person skilled in the art suchas, for example, reduction of the corresponding nitrile or acid orester, reaction of an appropriate organometallic or metallated specieswith N,N-dimethylformamide, general carbonylation methods known to theskilled person etc. Dicarbonyl compounds of formula (XXI) can either bepurchased from commercial suppliers (e.g. Sigma-Aldrich etc) or made byat least one of a number of standard methods known to the person skilledin the art such as, for example, by selenium-dioxide-mediated oxidationof the appropriate substrate as described in Rabjohn, N. Org. React,1976, 44, 261, or by the method outlined below under Method F.

Step 2:

-   -   where Z is selected from the group consisting of Cl, Br, I and        triflate

Compounds of formula (III) can be made, respectively, through thereaction of compounds of formula (XXXV) with boronic acids or boronicesters of formula (XXXVI) preferably under standard Suzuki couplingconditions such as reaction with a source of Pd⁰ such as Pd(OAc)₂reduced in situ using, for example, PPh₃, and a base such as CsF in asuitable solvent such as DMF. Heating may also be employed in thereaction. Boronic acids or boronic esters of formula (XXXVI) cangenerally be purchased from commercial suppliers (e.g. CombiBlocks (SanDiego, USA), San Diego, USA) but, in instances where boronic acids orboronic esters of formula (XXXVI) are not commercially available, theymay also be made by at least one of a number of standard methods knownto the person skilled in the art such as, for example, the reaction ofan appropriate organometallic species, e.g. an organolithium or Grignardspecies, with a borate ester followed by an optional hydrolysis of theproduct borate ester, cross-coupling of an appropriate halide with adiboronyl ester or diboronic acid, transmetallation of an appropriatestannane with boron tribromide followed by hydrolysis to thecorresponding boronic acid, etc.

An example of the use of Method C in the synthesis of 2-furanylimidazolecompounds of the invention is as follows (1-phenylpropane-1,2-dione iscommercially available from, inter alia, Sigma-Aldrich and5-bromo-2-furaldehyde is commercially available from, inter alia,Sigma-Aldrich):

Step 1:

Into a solution of 1-phenylpropane-1,2-dione 126 (4.03 g, 27.2 mmol, 1.0equiv.) in methanol (60 mL) was added 5-bromo-2-furaldehyde 127 (4.76 g,27.2 mmol, 1.0 equiv.) followed by ammonium acetate (16.8 g, 217.0 mmol,8.0 equiv.) and the reaction stirred at 65° C. for 2 h. The mixture wascooled, concentrated in vacuo, diluted with water (150 mL) and extractedwith dichloromethane (2×100 mL; 1×50 mL). The combined organic phaseswere washed with water (100 mL), passed through a phase separating fritand concentrated in vacuo. The desired product 128 was isolated aftercolumn chromatography on silica eluting with mixtures ofiso-hexane/ethyl acetate.

Yield: 6.58 g (80%); ¹H NMR (CDCl₃, 400 MHz): δ 7.57 (d, 2H, J=7.3 Hz),7.42 (dd, 2H, J=7.7, 7.7 Hz), 7.29 (dd, 1H, J=7.5, 7.5 Hz), 6.86 (d, 1H,J=3.3 Hz), 6.41 (d, 1H, J=3.3 Hz), 2.47 (s, 3H).

In the above-outlined reaction of Step 1, either of the startingmaterials (diketone or aldehyde) may be replaced by analogous startingmaterials containing corresponding functionality (e.g. the diketone withalternative diketones and the aromatic aldehyde with alternativearomatic aldehydes) in the same molar ratios to yield the analogousreaction product. For example, the diketone compound used can be otherthan an aryl diketone.

Step 2:

Stock solutions of intermediate 128 (0.29 M in deoxygenated DMF),Pd(OAc)₂ (0.045 M in deoxygenated DMF), PPh₃ (0.14 M in deoxygenatedDMF) and CsF (1.73 M in deoxygenated H₂O) were prepared. Each reactionvessel was charged with intermediate 3 (750 μL, 0.22 mmol, 1.0 equiv.),boronic acid/boronate ester (XXXVI) (0.30 mmol, 1.4 equiv.), PPh₃ (200μL, 0.03 mmol, 12 mol %), and CsF (375 μL, 0.65 mmol, 3.0 equiv.). Thesolution was sparged with nitrogen, Pd(OAc)₂ (200 μL, 4 mol %) added,the tubes flushed with nitrogen, sealed and stirred at 90° C. for 16 h.The reactions were cooled and diluted with water/brine (5 mL; 2:3) andethyl acetate (3 mL). The mixture was agitated in the reaction tube witha plastic pipette and the ethyl acetate layer separated. Centrifugationwas used to improve partition where poor phase separation occurred.Additional aliquots of ethyl acetate (2×2.0 mL) were added and theprocedure repeated. The combined ethyl acetate extracts wereconcentrated in vacuo using a Genevac, the residue dissolved in DMSO(1.5 mL) and purified by reversed phase preparative HPLC usingpreparative HPLC Procedure 11.

By means of example, the following compounds were synthesized by themethod outlined above (replacing the starting materials describedtherein with the appropriate analogues) and purified using preparativeHPLC Procedure 11.

Compound 1 below was synthesized in 37% yield over 2 steps from5-bromo-2-furaldehyde (commercially available from, inter alia,Sigma-Aldrich) and 1-phenylpropane-1,2-dione (also known asPhenyl-1,2-propanedione and commercially available from, inter alia,Sigma-Aldrich) followed by reaction in step 2 with2,4-dichlorophenylboronic acid (commercially available from CombiBlocks(San Diego, USA)) using the conditions outlined above.

¹H NMR (DMSO-d6, 400 MHz): δ 12.75 (s, 1H), 8.23 (d, 1H, J=8.6 Hz), 7.81(d, 1H, J=2.3 Hz), 7.75 (d, 1H, J=7.3 Hz), 7.69-7.64 (m, 2H), 7.64-7.57(m, 1H), 7.49 (dd, 1H, J=7.6, 7.6 Hz), 7.40 (d, 1H, J=3.5 Hz), 7.32 (dd,1H, J=7.2, 7.2 Hz), 7.07 (d, 1H, J=3.5 Hz), 2.53 (s, 3H); MS (ESI+): m/z369 (MH+; ³⁵Cl); Purity: 94.7%; RT: 4.11 min.

Compound 17 below was synthesized in 35% yield over 2 steps from5-bromo-2-furaldehyde (commercially available from, inter alia,Sigma-Aldrich) and 1-phenylpropane-1,2-dione (also known asPhenyl-1,2-propanedione and commercially available from, inter alia,Sigma-Aldrich) followed by reaction in step 2 with2-(trifluoromethyl)phenylboronic acid (commercially available fromCombiBlocks (San Diego, USA)) using the conditions outlined above.

Compound 31 below was synthesized in 52% yield over 2 steps from5-bromo-2-furaldehyde (commercially available from, inter alia,Sigma-Aldrich) and 1-phenylpropane-1,2-dione (also known asPhenyl-1,2-propanedione and commercially available from, inter alia,Sigma-Aldrich) followed by reaction in step 2 with4-methoxy-2-(trifluoromethyl)phenylboronic acid (commercially availablefrom CombiBlocks (San Diego, USA)) using the conditions outlined above.

Compound 31a below was synthesized in 6% yield over 2 steps from5-bromo-2-furaldehyde (commercially available from, inter alia,Sigma-Aldrich) and 1-phenylpropane-1,2-dione (also known asPhenyl-1,2-propanedione and commercially available from, inter alia,Sigma-Aldrich) followed by reaction in step 2 with5-fluoro-2-(trifluoromethyl)phenylboronic acid (commercially availablefrom CombiBlocks (San Diego, USA)) using the conditions outlined above.

Compound 32 below was synthesized in 6% yield over 2 steps from5-bromo-2-furaldehyde (commercially available from, inter alia,Sigma-Aldrich) and 1-phenylpropane-1,2-dione (also known asPhenyl-1,2-propanedione and commercially available from, inter alia,Sigma-Aldrich) followed by reaction in step 2 with4-chloro-2-(trifluoromethyl)phenylboronic acid (commercially availablefrom CombiBlocks (San Diego, USA)) using the conditions outlined above.

Compound 34 below was synthesized in 41% yield over 2 steps from5-bromo-2-furaldehyde (commercially available from, inter alia,Sigma-Aldrich) and 1-phenylpropane-1,2-dione (also known asPhenyl-1,2-propanedione and commercially available from, inter alia,Sigma-Aldrich) followed by reaction in step 2 with3-(trifluoromethoxy)phenylboronic acid (commercially available fromCombiBlocks (San Diego, USA)) using the conditions outlined above.

Compound 35 below was synthesized in 44% yield over 2 steps from5-bromo-2-furaldehyde (commercially available from, inter alia,Sigma-Aldrich) and 1-phenylpropane-1,2-dione (also known asPhenyl-1,2-propanedione and commercially available from, inter alia,Sigma-Aldrich) followed by reaction in step 2 with 3,5-bis(trifluoromethyl)phenylboronic acid (commercially available fromCombiBlocks (San Diego, USA)) using the conditions outlined above.

Compound 45 below was synthesized in 60% yield over 2 steps from5-bromo-2-furaldehyde (commercially available from, inter alia,Sigma-Aldrich) and 1-phenylpropane-1,2-dione (also known asPhenyl-1,2-propanedione and commercially available from, inter alia,Sigma-Aldrich) followed by reaction in step 2 with4-(trifluoromethyl)phenylboronic acid (commercially available fromCombiBlocks (San Diego, USA)) using the conditions outlined above.

Compound 61 below was synthesized in 59% yield over 2 steps from5-bromo-2-furaldehyde (commercially available from, inter alia,Sigma-Aldrich) and 1-phenylpropane-1,2-dione (also known asPhenyl-1,2-propanedione and commercially available from, inter alia,Sigma-Aldrich) followed by reaction in step 2 with o-tolylboronic acid(commercially available from CombiBlocks (San Diego, USA)) using theconditions outlined above.

Compound 62 below was synthesized in 11% yield over 2 steps from5-bromo-2-furaldehyde (commercially available from, inter alia,Sigma-Aldrich) and 1-phenylpropane-1,2-dione (also known asPhenyl-1,2-propanedione and commercially available from, inter alia,Sigma-Aldrich) followed by reaction in step 2 with2,6-dimethylphenylboronic acid (commercially available from CombiBlocks(San Diego, USA)) using the conditions outlined above.

Compound 71, below, was synthesized in 40% yield over 2 steps from5-bromo-2-furaldehyde (commercially available from, inter alia,Sigma-Aldrich) and 1-phenylpropane-1,2-dione (also known asPhenyl-1,2-propanedione and commercially available from, inter alia,Sigma-Aldrich) followed by reaction in step 2 with2-(dimethylamino)phenylboronic acid (commercially available fromCombiBlocks (San Diego, USA)) using the conditions outlined above.

Method D (General Procedure for the Synthesis of the Imidazoles in TwoSteps):

Step 1:

-   -   where Z is selected from the group consisting of Cl, Br, I and        triflate

Compounds of formula (XX) can be made by reaction of compounds offormula (XXXIV) with compounds of formula (XXXVI) in the presence of asource of Pd⁰ and a base preferably under standard Suzuki reactionconditions. Exemplary reaction conditions are (i) the reaction of theabove compounds with Pd(PPh)₃ and 2M aqueous Na₂CO₃ solution in asolvent mixture of toluene/ethanol and (ii) the reaction of the abovecompounds with Pd(dppf)Cl₂•CH₂Cl₂ and K₃PO₄ in a solvent mixture ofDME/water. Aldehydes of formula (XXXIV) can generally be purchased fromcommercial suppliers but, in instances where aldehydes of formula(XXXIV) are not commercially available, they may also be made by atleast one of a number of standard methods known to the person skilled inthe art such as, for example, reduction of the corresponding nitrile oracid or ester, reaction of an appropriate organometallic or metallatedspecies with N,N-dimethylformamide, general carbonylation methods knownto the skilled person etc. Boronic acids or boronic esters of formula(XXXVI) can generally be purchased from commercial suppliers (e.g.CombiBlocks (San Diego, USA), San Diego, USA) but, in instances whereboronic acids or boronic esters of formula (XXXVI) are not commerciallyavailable, they may also be made by at least one of a number of standardmethods known to the person skilled in the art such as, for example, thereaction of an appropriate organometallic species, e.g. an organolithiumor Grignard species, with a borate ester followed by an optionalhydrolysis of the product borate ester, cross-coupling of an appropriatehalide with a diboronyl ester or diboronic acid, transmetallation of anappropriate stannane with boron tribromide followed by hydrolysis to thecorresponding boronic acid, etc.

Step 2:

Compounds of Formula (III) may be made through the reaction of analdehyde of formula (XX) with a dicarbonyl compound of formula (XXI) inthe presence of a source of ammonia preferably under standard conditionssuch as heating in a solvent, for example an alcoholic solvent.Exemplary reaction conditions are (i) the reaction of the abovecompounds with ammonium acetate in either glacial acetic acid ormethanol and using a reaction temperature from 25 to 70° C.

Dicarbonyl compounds of formula (XXI) can either be purchased fromcommercial suppliers (for example, inter alia, Sigma-Aldrich (St. Louis,Mo., USA), Alfa Aesar (Schiltigheim, France), Acros Organics (Geel,Belgium), Key Organics (Camelford, UK), Matrix Scientific (Columbia,S.C., USA), Fluorochem (Hadfield, Derbyshire, UK) and Enamine (Kiev,Ukraine)) or made by at least one of a number of standard methods knownto the person skilled in the art such as, for example, byselenium-dioxide-mediated oxidation of the appropriate substrate asdescribed in Rabjohn, N. Org. React, 1976, 44, 261, or by the methodoutlined herein below under Method F.

By means of example, the following compounds were synthesized usingMethod D by means of the following specific reaction conditions:

Step 1—Suzuki Reaction: General Procedure

A mixture of the aldehyde (XXXIV) (0.523 mmol), the appropriate boronicacid or ester (XXXVI) (0.628 mmol), toluene (10 mL), EtOH (2.6 mL) and a2 M aq. Na₂CO₃ solution (15.4 mL) was degassed by bubbling argon for 30min. Then, Pd(PPh₃)₄ (36 mg, 0.0314 mmol) was added and the mixture wasstirred overnight at 80° C.

The reaction mixture was diluted with water (30 mL) and extracted withEtOAc (4×10 mL). Organic layers were combined and the solvent evaporatedto yield the crude product.

The crude product was purified by flash chromatography (SiO₂ column 10g—eluents n-Hexane/EtOAc=3/1). The appropriate fractions were combinedand the solvent evaporated to yield the desired purified aldehyde (XX)compound.

Step 2—Imidazole Formation: General Procedure

The product aldehyde (XX) from step 1 (0.382 mmol), NH₄OAc (294 mg, 3.82mmol) and the appropriate dicarbonyl compound (XXI) (0.382 mmol) werecombined and dissolved in 3.9 mL MeOH and heated at 60° C. overnight.

The solvent of the reaction mixture was evaporated to get the crudematerial which was purified by preparative HPLC Procedure #12. Theappropriate fractions were combined and lyophilized overnight giving thedesired final product (III).

Further compounds of the invention made by the above-outlined procedureare outlined herein below:

Compound 115 was synthesized in 24% yield over 2 steps through reactionin Step 1 of 5-Bromo-4-methyl-thiophene-2-carbaldehyde (purchased fromCombiBlocks (San Diego, USA)) and2-[2-(Trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(commercially available from, inter alia, TCI (TOKYO, JAPAN) Chemicals)followed by reaction in Step 2 with 2,3-Hexanedione (commerciallyavailable from multiple suppliers including, inter alia, Sigma-Aldrich)using the conditions outlined above.

Compound 113 was synthesized in 29% yield over 2 steps through reactionin Step 1 of 5-Bromo-thiophene-3-carbaldehyde (purchased fromCombiBlocks (San Diego, USA)) and2-[2-(Trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(commercially available from, inter alia, TCI (TOKYO, JAPAN) Chemicals)followed by reaction in Step 2 with 2,3-Hexanedione (commerciallyavailable from multiple suppliers including, inter alia, Sigma-Aldrich)using the conditions outlined above.

Compound 114 was synthesized in 36% yield over 2 steps through reactionin Step 1 of7-Bromo-2,3-dihydro-thieno[3,4-b][1,4]-dioxine-5-carbaldehyde (purchasedfrom Bepharm, Shanghai, China) and2-[2-(Trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(commercially available from, inter alia, TCI (TOKYO, JAPAN) Chemicals)followed by reaction in Step 2 with 2,3-Hexanedione (commerciallyavailable from multiple suppliers including, inter alia, Sigma-Aldrich)using the conditions outlined above.

Method E (General Procedure for the Synthesis of the Imidazoles):

Compounds of formula (III) can be made through the reaction of aldehydesof formula (XX) with dicarbonyl compounds of formula (XXI) in thepresence of a source of ammonia preferably under standard conditionssuch as heating in a solvent, for example an alcoholic solvent.Exemplary reaction conditions are (i) the reaction of the abovecompounds with ammonium acetate in either glacial acetic acid ormethanol and using a reaction temperature from 25 to 70° C.

Aldehydes of formula (XX) may be generated from esters of formula (XXXX)via a two step reduction/oxidation process preferably under standardconditions such as reduction of the ester group with a standard reducingagent (for example LiAlH₄ in diethyl ether) and oxidation of theresultant alcohol with a standard oxidizing agent for alcohol toaldehyde transformations (for example Dess-Martin Periodinane inCH₂Cl₂). Esters of formula (XXXX) can be made through Suzukicross-coupling reaction of esters of formula (XXXIX) with boronic acidsor boronic esters of formula (XXXVI) preferably under standard Suzukireaction conditions such as those mentioned in Method C above and estersof formula (XXXIX) can, in turn, be made from acids of formula (XXXVIII)preferably under standard esterification conditions such as reactionwith SOCl₂ in methanol at ambient (room) temperature for 16 h. Inaddition to —CH₃, or —CH₂CH₃, R″ may be also be C_(3to6)alkyl. Steps 3and 4 may be replaced by a single reduction step such to reduce ester(XXXX) directly to aldehyde (XX) using conditions known to the personskilled in the art.

An example of the use of Method E in the synthesis of 2-furanylimidazolecompounds of the invention is

By means of example, the following compounds were synthesized usingMethod E by means of the following specific reaction conditions:

Step 1—Esterification: General Procedure

To a solution of the starting carboxylic acid (XXXVIII) (3.141 mmol) inMeOH or EtOH (24 mL) was added thionyl chloride (1.13 mL). The reactionmixture was stirred at room temperature overnight.

The reaction mixture was evaporated. The crude product was re-dissolvedin DCM (10 mL) and the solvent evaporated again. This procedure wasrepeated 3 times to get the desired product (XXXIX) (either ethyl esteror methyl ester depending on solvent used).

Appropriate carboxylic acid starting materials (XXXVIII) are generallycommercially from suppliers such as, inter alia, Apollo Scientific,Manchester, UK. In instances where the appropriate starting carboxylicacids (XXXVIII) are not commercially available, they may also be made byat least one of a number of standard methods known to the person skilledin the art such as, for example, hydrolysis of the corresponding nitrileor ester, reaction of an appropriate organometallic or metallatedspecies with CO₂ or a CO₂ analogue, general carboxylation methods knownto the skilled person etc.

Step 2—Suzuki Reaction: General Procedure

A mixture of the ester (XXXIX) from Step 1 (0.523 mmol), the appropriatethe appropriate boronic acid or ester (XXXVI) (0.628 mmol), toluene (10mL), EtOH (2.6 mL) and a 2 M aq. Na₂CO₃ solution (15.4 mL) was degassedby bubbling argon for 30 min. Then, Pd(PPh₃)₄ (36 mg, 0.0314 mmol) wasadded and the mixture was stirred overnight at 80° C.

The reaction mixture was diluted with water (30 mL) and extracted withEtOAc (4×10 mL). Organic layers were combined and the solvent evaporatedto yield the crude product.

The crude product was purified by flash chromatography (SiO₂ column 10g—eluents n-Hexane/EtOAc=3/1). The appropriate fractions were combinedand the solvent evaporated to yield the desired purified compound(XXXX).

Appropriate boronic acids or boronic esters of formula (XXXVI) cangenerally be purchased from commercial suppliers (e.g. CombiBlocks (SanDiego, USA), San Diego, USA) but, in instances where boronic acids orboronic esters of formula (XXXVI) are not commercially available, theymay also be made by at least one of a number of standard methods knownto the person skilled in the art such as, for example, the reaction ofan appropriate organometallic species, e.g. an organolithium or Grignardspecies, with a borate ester followed by an optional hydrolysis of theproduct borate ester, cross-coupling of an appropriate halide with adiboronyl ester or diboronic acid, transmetallation of an appropriatestannane with boron tribromide followed by hydrolysis to thecorresponding boronic acid, etc.

Step 3—Reduction: General Procedure

To a cooled solution of LiAlH₄ (114 mg) in diethyl ether (2.7 mL) at 0°C. was added dropwise a solution of the carboxylic acid ester (XXXX)from step 2 (1.003 mmol) in diethyl ether (2.7 mL). The reaction mixturewas stirred at 0° C. for 1 hr.

The reaction mixture was slowly added to cooled water (50 mL) andextracted with EtOAc (5×30 mL). Organic layers were combined andevaporated to yield the desired product

Step 4—Oxidation: General Procedure

To a solution of the product alcohol from step 3 (0.136 mmol) in DCM(2.5 mL) was added Dess-Martin periodane (115 mg) at 0° C. The reactionmixture was stirred at room temperature for 30 min.

The reaction mixture was filtered through celite and the solvent wasevaporated. The residue was dissolved in EtOAc (50 mL) and washed withsat. NaHCO₃ solution (8×30 mL). The combined organic layers wereevaporated to yield the desired product (XX).

Step 5—Imidazole Formation: General Procedure

The aldehyde (XX) from step 4 (0.382 mmol), NH₄OAc (294 mg, 3.82 mmol)and the appropriate dione (XXI) (0.382 mmol) were combined and dissolvedin 3.9 mL MeOH and heated at 60° C. overnight.

The solvent of the reaction mixture was evaporated to get the crudematerial which was purified by preparative HPLC Procedure #12. Theappropriate fractions were combined and lyophilized overnight giving thedesired final product (III).

Appropriate diones (XXI) can either be purchased from commercialsuppliers (for example, inter alia, Sigma-Aldrich (St. Louis, Mo., USA),Alfa Aesar (Schiltigheim, France), Acros Organics (Geel, Belgium), KeyOrganics (Camelford, UK), Matrix Scientific (Columbia, S.C., USA),Fluorochem (Hadfield, Derbyshire, UK) and Enamine (Kiev, Ukraine)) ormade by at least one of a number of standard methods known to the personskilled in the art such as, for example, by selenium-dioxide-mediatedoxidation of the appropriate substrate as described in Rabjohn, N. Org.React, 1976, 44, 261, or by the method outlined herein below underMethod F.

Further compounds of the invention made by the above-outlined procedureare outlined herein below:

Compound 72 was synthesized in 18% yield over 5 steps from5-Bromo-furan-3-carboxylic acid (purchased from Apollo Scientific,Manchester UK) using the conditions outlined above.2-[2-(Trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas used as the appropriate boronic ester in step 2 (commerciallyavailable from, inter alia, TCI (TOKYO, JAPAN) Chemicals and CombiBlocks(San Diego, USA)). In step 5, 1-Phenyl-1,2-propanedione was used as theappropriate dione (commercially available from, inter alia,Sigma-Aldrich).

Compound 112 was synthesized in 22% yield over 5 steps from5-Bromo-furan-3-carboxylic acid (purchased from Apollo Scientific) usingthe conditions outlined above.2-[2-(Trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas used as the appropriate boronic ester in step 2 (commerciallyavailable from, inter alia, TCI (TOKYO, JAPAN) Chemicals). In step 5,2,3-Hexanedione was used as the appropriate dione (commerciallyavailable from multiple suppliers including, inter alia, Sigma-Aldrich).

Method F (General Procedure for the Synthesis of the DicarbonylCompounds and their Subsequent Conversion to Imidazoles):

When one of R¹ or R² in a compound of the present invention is anunsubstituted or substituted phenyl ring and the other is a methylgroup, when compounds of formula (L) are not commercially available theymay be made via the following process. This general procedure may alsobe useful in some instances for the synthesis ofnon-aryl-ring-containing dicarbonyl compounds.

Diketo compounds of formula (L) may be made from vinyl ether compoundsof formula (XXXXIX) preferably under standard conditions etherhydrolysis conditions such as treatment with aqueous acid, for examplehydrochloric acid. Vinyl ether compounds of formula (XXXXIX) may be madevia reaction of Weinreb amides of formula (XXXXVIII) preferably understandard anionic conditions such as reaction of the Weinreb amide offormula (XXXXVIII) with the corresponding metalated, for examplelithiated, vinyl ether, i.e. through reaction with the vinyl anion.Weinreb amides of formula (XXXXVIII) may be made from acids of formula(XXXXVII) preferably under standard conditions such as amide coupling ofN,O-dimethylhydroxylamine hydrochloride and acids of formula (XXXXVII)using a standard amide coupling agent such as CDI and a base, forexample an organic base such as triethylamine, in an appropriate solventsuch as CH₂Cl₂.

Carboxylic acid starting materials of formula (XXXXVII) can generally bepurchased from commercial suppliers (e.g. Sigma-Aldrich, ApolloScientifc, CombiBlocks (San Diego, USA), Enamine (Kiev, Ukraine) etc).In instances where the appropriate starting carboxylic acids (XXXXVII)are not commercially available, they may also be made by at least one ofa number of standard methods known to the person skilled in the art suchas, for example, hydrolysis of the corresponding nitrile or ester,reaction of an appropriate organometallic or metallated species with CO₂or a CO₂ analogue, general carboxylation methods known to the skilledperson etc.

Exemplary general experimental protocols for the above reaction schemeare provided as follows:

Step A:

To a suspension of corresponding acid (XXXXVII) (64 mmol) in DCM (150mL) CDI (1,1′-Carbonyldiimidazole) (11 g, 68 mmol) was added in severalportions under cooling with ice-bath, and the resulting mixture wasstirred until the evolution of gas was ceased. Freshly distilled Et₃N(14mL, 100 mmol) followed by N,O-dimethylhydroxylamine hydrochloride (6.8g, 70 mmol) were added, and the resulting mixture was stirred for 16 h.The organic solution was washed with water (2×30 mL), 2N HCl solution,dried and evaporated. An average yield of (XXXXVIII) was 75-80%.

Step B:

To a degassed solution of ethyl vinyl ether (9 mL, 94 mmol) in THF (300mL) t-BuLi (31 mL, 1.6M in pentane, 50 mmol) was added drop by dropmaintaining the temperature below −65° C. The above obtained solutionwas warmed up to 0° C. during 1 h, stirred for 10 min, cooled to −65°C., and treated with a solution of (XXXXVIII) (50 mmol) in THF (100 mL).The mixture was stirred overnight without cooling, neutralized with asaturated NH₄Cl solution (500 mL), and extracted with MTBE (3×50 mL).The combined organic layers were washed with water (3×20 mL), dried andconcentrated to afford pure (XXXXIX) as a dark oily residue which wasimmediately used in the next step.

Step C:

A solution of intermediate (XXXXIX) in a mixture of MeOH (100 mL) andHCl (2N, 50 mL) was refluxed overnight. Then it was cooled,concentrated, and aqueous phase was extracted with DCM (2×50 mL). Thecombined organic layers were washed with water (1×20 mL), aqueoussolution of sodium bicarbonate, dried, and concentrated. The yield of(L) was 30-40% over 2 steps. The dicarbonyl compounds of formula (L)obtained from step C may then be employed to make the compounds of theinvention via one of the methods listed herein which utilizes dicarbonylcompounds in the synthesis of compounds of the invention. An example ofsuch a reaction is provided in Step D below.

Step D:

Imidazole compounds of formula (LI) may be made through the reaction ofan aldehyde of formula (XX) with a dicarbonyl compound of formula (L) inthe presence of a source of ammonia preferably under standard conditionssuch as heating in a solvent, for example an acidic solvent such asacetic acid. The following outlines an exemplary general procedure forthis transformation:

A mixture of aldehyde (XX) (5.5 mmol), dicarbonyl intermediate from stepC (L) (5.5 mmol) and ammonium acetate (6 g, 52 mmol) in HOAc (50 mL) wasrefluxed for 16 h. Then it was evaporated to dryness, and residue wasdissolved in EtOAc. The resulting solution was washed with water, sodiumbicarbonate, dried over sodium sulfate, and concentrated. The crudematerial was purified by column chromatography (silica gel,MTBE-hexane).

Aldehydes of formula (XX) are generally commercially available (forexample from, inter alia, Sigma-Aldrich (St. Louis, Mo., USA), AlfaAesar (Schiltigheim, France), Acros Organics (Geel, Belgium), KeyOrganics (Camelford, UK), Matrix Scientific (Columbia, S.C., USA),Fluorochem (Hadfield, Derbyshire, UK) and Enamine (Kiev, Ukraine)) but,when they are not commercially available, they may also be made by atleast one of a number of standard methods known to the person skilled inthe art such as, for example, reduction of the corresponding nitrile oracid or ester, reaction of an appropriate organometallic or metallatedspecies with N,N-dimethylformamide, general carbonylation methods knownto the skilled person etc. Aldehydes of formula (XX) may also be made byfurther methods such as, for example, those outlined herein under thecorresponding reaction step in Method D (step 1), in Method H or by anynumber of the steps (as required depending on the available startingmaterial) leading to such aldehydes in Method E herein.

Examples of the invention can be made according to the above-outlinedsteps A to D where, although the absolute quantities of startingmaterials, reactants and reagents used therein may deviate from thoseoutlined above for steps A to D, within any given step the relativemolar quantities of starting materials, reactants and reagents as wellas concentrations are consistent with those stipulated in steps A to Dabove.

By means of example, the following compounds of the invention were madeaccording to Method F as outlined above.

Compound 60 below was synthesized in 7% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 5-(3-fluoro-2-methylphenyl)furan-2-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 39 below was synthesized in 56% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and5-[4-chloro-3-(trifluoromethyl)phenyl]furan-2-carbaldehyde (commerciallyavailable from Enamine (Kiev, Ukraine)) using 5.5 mmol of the aldehydeSM using the conditions outlined above.

Compound 3 below was synthesized in 7% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 5-(2-Chlorophenyl)furfural (commercially availablefrom, inter alia, Sigma-Aldrich) using 5.5 mmol of the aldehyde SM usingthe conditions outlined above.

Compound 45 below was synthesized in 91% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 5-[4-(trifluoromethyl)phenyl]furan-2-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 2 below was synthesized in 93% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 5-(2,3-dichlorophenyl)furan-2-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 57 below was synthesized in 68% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 2-(4-methylphenyl)-1,3-oxazole-4-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 8 below was synthesized in 14% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and2,5-dimethyl-1-(4-methylphenyl)-1H-pyrrole-3-carbaldehyde (commerciallyavailable from Enamine (Kiev, Ukraine)) using 5.5 mmol of the aldehydeSM using the conditions outlined above.

Compound 11 below was synthesized in 96% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 2-(4-methylphenyl)-1,3-thiazole-4-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 73 below was synthesized in 31% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 2-phenyl-2H-1,2,3-triazole-4-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 14 below was synthesized from 1-Phenyl-1,2-propanedione(commercially available from, inter alia, Sigma-Aldrich) and2-(3-bromophenyl)-1,3-thiazole-4-carbaldehyde (commercially availablefrom Enamine (Kiev, Ukraine)) using 5.5 mmol of the aldehyde SM usingthe conditions outlined above.

Compound 56 below was synthesized in 24% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 2-(4-methylphenyl)-1,3-thiazole-4-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 58 below was synthesized from 1-Phenyl-1,2-propanedione(commercially available from, inter alia, Sigma-Aldrich) and2,5-dimethyl-1-[4-(propan-2-yl)phenyl]-1H-pyrrole-3-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 36 below was synthesized in 32% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and2,5-dimethyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 59 below was synthesized in 16% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and1-(2,3-dihydro-1H-inden-5-yl)-2,5-dimethyl-1H-pyrrole-3-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 52 below was synthesized in 43% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 5-(4-methylphenyl)furan-2-carbaldehyde (commerciallyavailable from Enamine (Kiev, Ukraine) using 5.5 mmol of the aldehyde SMusing the conditions outlined above.

Compound 54 below was synthesized in 25% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 5-(p-tolyl)thiophene-2-carbaldehyde (commerciallyavailable from Enamine (Kiev, Ukraine)) using 5.5 mmol of the aldehydeSM using the conditions outlined above.

Compound 7 below was synthesized in 21% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 5-(4-fluorophenyl)thiophene-2-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 15 below was synthesized from 1-Phenyl-1,2-propanedione(commercially available from, inter alia, Sigma-Aldrich) and5-(2-fluorophenyl)thiophene-2-carbaldehyde (commercially available fromEnamine (Kiev, Ukraine)) using 5.5 mmol of the aldehyde SM using theconditions outlined above.

Compound 46 below was synthesized in 45% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 6 below was synthesized in 47% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 5-(4-chlorophenyl)thiophene-2-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 10 below was synthesized in 11% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and2,5-dimethyl-1-(2,3,4-trifluorophenyl)-1H-pyrrole-3-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 55 below was synthesized from 1-Phenyl-1,2-propanedione(commercially available from, inter alia, Sigma-Aldrich) and2-(4-methylphenyl)-1,3-thiazole-5-carbaldehyde (commercially availablefrom Enamine (Kiev, Ukraine)) using 5.5 mmol of the aldehyde SM usingthe conditions outlined above.

Compound 12 below was synthesized in 58% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 5-(3-chlorophenyl)thiophene-2-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 33 below was synthesized in 7% yield (yield for final step)from 1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 1-(2-trifluoromethylphenyl)-1H-pyrrole-3-carbaldehydeusing 5.5 mmol of the aldehyde SM using the conditions outlined above.

1-(2-trifluoromethylphenyl)-1H-pyrrole-3-carbaldehyde was notcommercially available but instead synthesized through arylation of1H-pyrrole-3-carbaldehyde (commercially available from Sigma, Enamine(Kiev, Ukraine) etc.) with 2-Bromobenzotrifluoride (commerciallyavailable from Sigma, Enamine (Kiev, Ukraine) etc.) as follows:

A mixture of 1H-pyrrole-3-carbaldehyde (50 mmol),2-Bromobenzotrifluoride (50 mmol) and potassium carbonate (50 mmol) inDMF (25 mL) was stirred at 80° C. until reaction complete by TLCanalysis. The mixture was treated with water and extracted with DCM. Theorganics were washed with brine, dried, and concentrated. The resultantsolids were recrystallized from 2-propanol to yield1-(2-trifluoromethylphenyl)-1H-pyrrole-3-carbaldehyde in 80-85% puritywhich was used in the next steps without further purification.

Compound 42 below was synthesized in 45% yield (yield for step D) from4-fluorobenzoic acid (commercially available from, inter alia, Enamine(Kiev, Ukraine)) and5-[4-chloro-3-(trifluoromethyl)phenyl]furan-2-carbaldehyde (commerciallyavailable from Enamine (Kiev, Ukraine)) using 5.5 mmol of the aldehydeSM using the conditions outlined above.

Compound 27 below was synthesized in 23% yield (yield for step D) from4-Ethynylbenzoic acid (commercially available from, inter alia,Sigma-Aldrich (St. Louis, Mo., USA)) and5-[2-(Trifluoromethyl)phenyl]furfural (commercially available from,inter alia, Sigma-Aldrich (St. Louis, Mo., USA)) using 5.5 mmol of thealdehyde SM using the conditions outlined above.

Compound 13 below was synthesized in 29% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 5-(3-bromophenyl)thiophene-2-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 9 below was synthesized in 46% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and2,5-dimethyl-1-(2,4-difluorophenyl)-1H-pyrrole-3-carbaldehyde(commercially available from Enamine (Kiev, Ukraine)) using 5.5 mmol ofthe aldehyde SM using the conditions outlined above.

Compound 53 below was synthesized in 81% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 5-(4-ethylphenyl)furan-2-carbaldehyde (commerciallyavailable from Enamine (Kiev, Ukraine)) using 5.5 mmol of the aldehydeSM using the conditions outlined above.

Compound 74 below was synthesized in 62% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich) and 5-phenylthiophene-2-carbaldehyde (commerciallyavailable from Enamine (Kiev, Ukraine)) using 5.5 mmol of the aldehydeSM using the conditions outlined above.

By means of example, the following compounds of the invention were madeaccording to Method F as outlined above wherein the aldehyde startingmaterial required in step D was synthesized in accordance with Method Hof the present application.

Compound 19 below was synthesized in 20% yield (yield for step D ofMethod F) from 2-chlorobenzoic acid (commercially available from, interalia, Enamine (Kiev, Ukraine)) and5-[2-(trifluoromethoxy)phenyl]furan-2-carbaldehyde using 5.5 mmol usingthe conditions outlined above.5-[2-(trifluoromethoxy)phenyl]furan-2-carbaldehyde was made from[2-(trifluoromethoxy)phenyl]boronic acid (commercially available fromEnamine (Kiev, Ukraine)) and 5-bromofuran-2-carbaldehyde (commerciallyavailable from Enamine (Kiev, Ukraine)) using Method H of the presentinvention.

Compound 20 below was synthesized in 16% yield (yield for step D ofMethod F) from 2-chlorobenzoic acid (commercially available from, interalia, Enamine (Kiev, Ukraine)) and5-[2-(trifluoromethyl)phenyl]furan-2-carbaldehyde using 5.5 mmol of thealdehyde SM using the conditions outlined above.5-[2-(trifluoromethyl)phenyl]furan-2-carbaldehyde was made from[2-(trifluoromethyl)phenyl]boronic acid (commercially available fromEnamine (Kiev, Ukraine)) and 5-bromofuran-2-carbaldehyde (commerciallyavailable from Enamine (Kiev, Ukraine)) using Method H of the presentinvention.

Compound 21 below was synthesized in 23% yield (yield for step D ofMethod F) from 3-chlorobenzoic acid (commercially available from, interalia, Enamine (Kiev, Ukraine)) and5-[2-(trifluoromethoxy)phenyl]furan-2-carbaldehyde using 5.5 mmol of thealdehyde using the conditions outlined above.5-[2-(trifluoromethoxy)phenyl]furan-2-carbaldehyde was made from[2-(trifluoromethoxy)phenyl]boronic acid (commercially available fromEnamine (Kiev, Ukraine)) and 5-bromofuran-2-carbaldehyde (commerciallyavailable from ENAMINE (KIEV, UKRAINE)) using Method H of the presentinvention.

Compound 22 below was synthesized in 21% yield (yield for step D ofMethod F) from 3-chlorobenzoic acid (commercially available from, interalia, Enamine (Kiev, Ukraine)) and5-[2-(trifluoromethyl)phenyl]furan-2-carbaldehyde using 5.5 mmol of thealdehyde SM using the conditions outlined above.5-[2-(trifluoromethyl)phenyl]furan-2-carbaldehyde was made from[2-(trifluoromethyl)phenyl]boronic acid (commercially available fromEnamine (Kiev, Ukraine)) and 5-bromofuran-2-carbaldehyde (commerciallyavailable from Enamine (Kiev, Ukraine)) using Method H of the presentinvention.

Compound 37 below was synthesized in 37% yield (yield for step D) from4-fluorobenzoic acid (commercially available from, inter alia, Enamine(Kiev, Ukraine)) and 5-[3-(trifluoromethoxy)phenyl]furan-2-carbaldehydeusing 5.5 mmol of the aldehyde SM using the conditions outlined above.5-[3-(trifluoromethoxy)phenyl]furan-2-carbaldehyde was made from(5-formylfuran-2-yl)boronic acid (commercially available from TCI(TOKYO, JAPAN)) and 3-(Trifluoromethoxy)iodobenzene (commerciallyavailable from Enamine (Kiev, Ukraine)) using Method H of the presentinvention.

Compound 44 below was synthesized in 42% yield (yield for step D ofMethod F) from 4-chlorobenzoic acid (commercially available from, interalia, Enamine (Kiev, Ukraine)) and5-[4-chloro-3-(trifluoromethoxy)phenyl]furan-2-carbaldehyde using 5.5mmol of the aldehyde SM using the conditions outlined above.5-[4-chloro-3-(trifluoromethoxy)phenyl]furan-2-carbaldehyde was madefrom (5-formylfuran-2-yl)boronic acid (commercially available from TCI(TOKYO, JAPAN)) and 4-bromo-1-chloro-2-(trifluoromethoxy)benzene(commercially available from Fluorochem (Hadfield, Derbyshire, UK))using Method H of the present invention.

Compound 16 below was synthesized in 27% yield (yield for step D) from4-fluorobenzoic acid (commercially available from, inter alia, Enamine(Kiev, Ukraine)) and 5-(2,4-dichlorophenyl)furan-2-carbaldehyde using5.5 mmol of the aldehyde SM using the conditions outlined above.5-(2,4-dichlorophenyl)furan-2-carbaldehyde was made from(2,4-dichlorophenyl)boronic acid (commercially available from Enamine(Kiev, Ukraine)) and 5-bromofuran-2-carbaldehyde (commercially availablefrom Enamine (Kiev, Ukraine)) using Method H of the present invention.

Compound 47 below was synthesized in 16% yield (yield for step D ofMethod F) from 4-chlorobenzoic acid (commercially available from, interalia, Enamine (Kiev, Ukraine)) and5-[4-(trifluoromethyl)phenyl]furan-2-carbaldehyde using 5.5 mmol of thealdehyde SM using the conditions outlined above.5-[4-(trifluoromethyl)phenyl]furan-2-carbaldehyde was made from(5-formylfuran-2-yl)boronic acid (commercially available from TCI(TOKYO, JAPAN)) and 1-bromo-4-(trifluoromethyl)benzene (commerciallyavailable from Sigma-Aldrich (St. Louis, Mo., USA)) using Method H ofthe present invention.

Compound 48 below was synthesized in 61% yield (yield for step D ofMethod F) from 4-chlorobenzoic acid (commercially available from, interalia, Enamine (Kiev, Ukraine)) and5-[4-(trifluoromethoxy)phenyl]furan-2-carbaldehyde using 5.5 mmol of thealdehyde SM using the conditions outlined above.5-[4-(trifluoromethoxy)phenyl]furan-2-carbaldehyde was made from(5-formylfuran-2-yl)boronic acid (commercially available from TCI(TOKYO, JAPAN)) and 1-bromo-4-(trifluoromethoxy)benzene (commerciallyavailable from ENAMINE (KIEV, UKRAINE)) using Method H of the presentinvention.

Compound 43 below was synthesized in 35% yield (yield for step D) from4-fluorobenzoic acid (commercially available from, inter alia, Enamine(Kiev, Ukraine)) and5-[4-chloro-3-(trifluoromethoxy)phenyl]furan-2-carbaldehyde using 5.5mmol of the aldehyde SM using the conditions outlined above.5-[4-chloro-3-(trifluoromethoxy)phenyl]furan-2-carbaldehyde was madefrom (5-formylfuran-2-yl)boronic acid (commercially available from TCI(TOKYO, JAPAN)) and 4-bromo-1-chloro-2-(trifluoromethoxy)benzene(commercially available from Fluorochem (Hadfield, Derbyshire, UK))using Method H of the present invention.

Compound 41 below was synthesized in 40% yield (yield for step D) from1-Phenyl-1,2-propanedione (commercially available from, inter alia,Sigma-Aldrich (St. Louis, Mo., USA)) and5-[4-chloro-3-(trifluoromethoxy)phenyl]furan-2-carbaldehyde using 5.5mmol of the aldehyde SM using the conditions outlined above.5-[4-chloro-3-(trifluoromethoxy)phenyl]furan-2-carbaldehyde was madefrom (5-formylfuran-2-yl)boronic acid (commercially available from TCI(TOKYO, JAPAN)) and 4-bromo-1-chloro-2-(trifluoromethoxy)benzene(commercially available from Fluorochem (Hadfield, Derbyshire, UK))using Method H of the present invention.

Compound 51 below was synthesized from 4-fluorobenzoic acid(commercially available from, inter alia, Enamine (Kiev, Ukraine)) and5-(2-chloro-4-(trifluoromethoxy)phenyl)furan-2-carbaldehyde using 5.5mmol of the aldehyde SM using the conditions outlined above.5-(2-chloro-4-(trifluoromethoxy)phenyl)furan-2-carbaldehyde was madefrom (5-formylfuran-2-yl)boronic acid (commercially available from TCI(TOKYO, JAPAN)) and 1-Bromo-2-chloro-4-(trifluoromethoxy)benzene(commercially available from Enamine (Kiev, Ukraine)) using Method H ofthe present invention.

Compound 49 below was synthesized in from 4-fluorobenzoic acid(commercially available from, inter alia, Enamine (Kiev, Ukraine)) and5-(3-chloro-4-(trifluoromethyl)phenyl)furan-2-carbaldehyde using 5.5mmol of the aldehyde SM using the conditions outlined above.5-(3-chloro-4-(trifluoromethyl)phenyl)furan-2-carbaldehyde was made from(5-formylfuran-2-yl)boronic acid (commercially available from TCI(TOKYO, JAPAN)) and 4-bromo-2-chloro-1-(trifluoromethyl)benzene(commercially available from TCI (TOKYO, JAPAN)) using Method H of thepresent invention.

Compound 50 below was synthesized from 4-chlorobenzoic acid(commercially available from, inter alia, Enamine (Kiev, Ukraine)) and5-(3-chloro-4-(trifluoromethoxy)phenyl)furan-2-carbaldehyde using 5.5mmol of the aldehyde SM using the conditions outlined above.5-(3-chloro-4-(trifluoromethoxy)phenyl)furan-2-carbaldehyde was madefrom (5-formylfuran-2-yl)boronic acid (commercially available from TCI(TOKYO, JAPAN)) and 4-bromo-2-chloro-1-(trifluoromethoxy)benzene(commercially available from Fluorochem (Hadfield, Derbyshire, UK))using Method H of the present invention.

Method G (General Procedure for the Synthesis of the Imidazoles):

In certain cases where one of R¹ or R² in a compound of the presentinvention is H and the other is an unsubstituted or substituted phenylring, compounds of the present invention may be made via the followingprocess.

Compounds of formula (LIV) may be made through Suzuki coupling reactionof a boronic acid/ester of formula (XXXVI) with an imidazole of formula(LIII) preferably via standard Suzuki reaction conditions such as thosedescribed in Step 2 of Method C hereinabove. Imidazoles of formula(LIII) may be made through cyclization of dicarbonyl compounds offormula (LII) in the presence of a source of ammonia, for exampleammonium acetate, preferably using standard cond H is for suchcyclizations such as heating over a prolonged period in a high boilingsolvent, for example xylene, with a system designed to remove any watergenerated, for example a Dean-Stark apparatus. Dicarbonyl compounds offormula (LII) may be made from acids of formula (XXXVIII) preferablythrough standard alkylation reaction with the appropriate 1-arylethanonewhich is furnished with an appropriate leaving group, for example abromine atom, at the alkyl position adjacent to the ketone. Suchconditions may involve initially forming the anion of the acid offormula (XXXVIII) preferably under standard conditions such as stirringwith base in an appropriate solvent followed by reaction of theresultant carboxylate salt with the appropriate alkylating agent, forexample a 2-bromo-1-arylethanone.

Carboxylic acid starting materials of formula (XXXVIII) can generally bepurchased from commercial suppliers (e.g. Sigma-Aldrich (St. Louis, Mo.,USA), Apollo Scientifc, CombiBlocks (San Diego, USA), Enamine (Kiev,Ukraine) etc). In instances where the appropriate starting carboxylicacids (XXXVIII) are not commercially available, they may also be made byat least one of a number of standard methods known to the person skilledin the art such as, for example, hydrolysis of the corresponding nitrileor ester, reaction of an appropriate organometallic or metallatedspecies with CO₂ or a CO₂ analogue, general carboxylation methods knownto the skilled person etc.

Boronic acids or boronic esters of formula (XXXVI) can generally bepurchased from commercial suppliers (e.g. CombiBlocks (San Diego, USA))but, in instances where boronic acids or boronic esters of formula(XXXVI) are not commercially available, they may also be made by atleast one of a number of standard methods known to the person skilled inthe art such as, for example, the reaction of an appropriateorganometallic species, e.g. an organolithium or Grignard species, witha borate ester followed by an optional hydrolysis of the product borateester, cross-coupling of an appropriate halide with a diboronyl ester ordiboronic acid, transmetallation of an appropriate stannane with borontribromide followed by hydrolysis to the corresponding boronic acid,etc.

The appropriate alkylating agents, for example a 2-halo-1-arylethanonescan generally be purchased from commercial suppliers (e.g. Enamine(Kiev, Ukraine), Alfa Aesar (Schiltigheim, France) and others) but, ininstances where 2-halo-1-arylethanones are not commercially available,they may also be made by at least one of a number of standard methodsknown to the person skilled in the art such as, for example,Friedel-Krafts acylation reaction of the appropriate aryl ring with ahaloacetyl halide preferably under standard conditions, or halogenationof the methyl group of an appropriate acetophenone preferably understandard conditions.

A general example of the use of Method G to furnish compounds of theinvention is as follows

Step F:

A solution of 5-bromo-furane-2-carboxylic acid 130 (5 g, 26 mmol) inEtOH (200 mL) was combined with potassium carbonate (3.5 g, 27.8 mmol).The resulting suspension was stirred for 30 min, evaporated to dryness,and solids were suspended in MeCN (300 mL). To a stirred suspension2-bromo-1-(o-tolyl)ethanone (3.48 g, 26 mmol) was added in one portion,and resulting system was stirred for 24 h at room temperature. Thereaction mixture was filtered, evaporated to dryness, and used as is inthe next step.

Step G:

To a solution of compound 131 obtained from step F (8 g, 24.7 mmol) inxylene (600 mL) ammonium acetate (39 g, 50.6 mmol) was added, and theresulting mixture was refluxed for 1 week with Dean-Stark trap. Duringthis week additional portions of ammonium acetate (3×20 g) were addedeach 2 days. After cooling down to r.t. the mixture was diluted withEtOAc (500 mL). The organic layer was washed with water, saturatedNaHCO₃ solution, brine, dried, and concentrated. The residue waspurified by column chromatography (silica gel, MTBE/hexane) to obtainpure derivative 132 (900 mg, 2.97 mmol, 12% yield).

Step H:

A round-bottomed flask was charged with compound 132 obtained from stepG (250 mg, 825 μmol), the appropriate boronic acid (LV) (900 μmol),sodium carbonate (190 mg, 1.8 mmol), Pd(dppf)₂ (5 mol %, 30 mg), DME (40mL), and water (10 mL). The reaction mixture was stirred at 80° C. for16 h and then diluted with EtOAc. The organic phase was washed withwater, brine, dried, and evaporated. The residue was purified by flashcolumn chromatography on silica gel (MTBE-hexane). Yield of (LVI) 10 to50%.

Examples of the invention may be made according to the above-outlinedsteps F to H where, although the absolute quantities of startingmaterials, reactants and reagents used therein may deviate from thoseoutlined above for steps F to H, within any given step the relativemolar quantities of starting materials, reactants and reagents as wellas concentrations are consistent with those stipulated in steps F to Habove.

By means of example, the following compounds of the invention were madeaccording to Method G as outlined above.

Compound 66 below was synthesized in 15% yield (yield for final step)from 2-bromo-1-(o-tolyl)ethanone (commercially available from Enamine(Kiev, Ukraine)) and 5-bromo-furan-2-carboxylic acid (commerciallyavailable from Enamine (Kiev, Ukraine)) using 26 mmol of the acid SMfollowed by reaction in step H with (2-(trifluoromethoxy)phenyl)boronicacid (commercially available from Enamine (Kiev, Ukraine)) using theconditions outlined above.

Compound 69 below was synthesized in 35% yield (yield for final step)from 2-bromo-1-(o-tolyl)ethanone (commercially available from Enamine(Kiev, Ukraine)) and 5-bromo-furan-2-carboxylic acid (commerciallyavailable from Enamine (Kiev, Ukraine)) using 26 mmol of the acid SMfollowed by reaction in step H with (2-(trifluoromethyl)phenyl)boronicacid (commercially available from Enamine (Kiev, Ukraine)) using theconditions outlined above.

It is also possible that compounds of the present invention besynthesized using only parts of the chemistry of Method G. In suchcases, the structures of the starting materials vary slightly from thosedepicted in the general scheme for Method G shown above. For example, incases where an appropriate carboxylic acid starting material in which zdoes not represent Cl, Br, I or triflate but instead already the desired‘B’ group to be present in the final compound is available, the finalstep (step H) of Method G may not be necessary to access the compoundsof the invention. In such a case, however, steps F and G of Method G maystill be employed to convert the appropriate carboxylic acid startingmaterial into a compound of the invention through reaction with theappropriate reaction partner in step F followed by closure of theimidazole ring in step G.

By means of example, the following compounds were synthesized by such aprocess in which step H of method G was not necessary as the structuralelement which step H would have been intended to have introduced (the‘B’ group) was already present in the starting carboxylic acid (i.e. ‘z’in the starting acid is represented by the ‘B’ group and not by Cl, Br,I, or triflate):

Compound 67 below was synthesized in from2-bromo-1-(2-chlorophenyl)ethan-1-one (commercially available fromEnamine (Kiev, Ukraine)) and5-[(2-(trifluoromethoxy)phenyl)furan]-2-carboxylic acid (commerciallyavailable from Enamine (Kiev, Ukraine)) using 26 mmol of the acid SMusing the conditions outlined above.

Compound 68 below was synthesized in from2-bromo-1-(2,4-dichlorophenyl)ethanone (commercially available fromSigma-Aldrich (St. Louis, Mo., USA)) and5-(2-(trifluoromethoxy)phenyl)furan-2-carboxylic acid (commerciallyavailable from Enamine (Kiev, Ukraine)) using 26 mmol of the acid SMusing the conditions outlined above.

Method H (Alternative Procedure for the Synthesis of Compounds ofFormula (XX)):

An alternative procedure for the synthesis of aldehydes of formula XX isoutlined below. Aldehydes of formula XX made via this method may then beused in any of the Methods listed herein which use aldehydes of formulaXX to synthesise the compounds of the invention.

Aldehydes of formula (XX) may be made via Suzuki cross-coupling reactionof aldehydes of formula (LVIII) and compounds of formula (LVII)preferably under standard Suzuki reaction conditions such as thoseoutlined in Method C above.

Aldehydes of formula (LVIII) are generally commercially available fromsupplier such as, for example, Enamine (Kiev, Ukraine) or Sigma-Aldrich(St. Louis, Mo., USA) but in instances where aldehydes of formula(LVIII) are not commercially available they may be made by at least oneof a number of standard methods known to the person skilled in the artsuch as, for example, reduction of the corresponding nitrile or acid orester, reaction of an appropriate organometallic or metallated specieswith N,N-dimethylformamide, general carbonylation methods known to theskilled person etc. Alternatively, in some instances the boronicester/acid functionality may be introduced into an appropriate startingmaterial to deliver aldehydes of formula (LVIII) by at least one of anumber of standard methods known to the person skilled in the art suchas, for example, cross-coupling of an appropriate halide with adiboronyl ester or diboronic acid.

Aryl halides or triflates of formula (LVII) are generally commerciallyavailable from supplier such as, for example, Enamine (Kiev, Ukraine),Sigma-Aldrich (St. Louis, Mo., USA), Apollo Scientifc etc but ininstances where aryl halides or triflates of formula (LVII) are notcommercially available they may be made by at least one of a number ofstandard methods known to the person skilled in the art such as, forexample, electrophilic aromatic substitution reaction with anelectrophilic source of the desired halogen or, in the case oftriflates, reaction of the corresponding hydroxyl compound with triflicanhydride.

Examples of aldehydes of formula (XX) made by this method include

Step I:

A glass vial with magnetic stir bar was charged with ethyl4-bromo-3-(trifluoromethyl)benzoate (5.94 g, 20 mmol), Pd(PPh₃)₄ (600mg), dimethoxyethane (40 mL), sodium carbonate (4.25 g, 40 mmol), andwater (20 mL). The vial was filled with argon, capped, and stirred for15 min. Then it was opened and solution of (5-formylfuran-2-yl)boronicacid 133 (3.5 g, 25 mmol) in ethanol (40 mL) was added. The vial wasfilled with argon, capped, and heated at 90° C. for 7 h under stirring.The reaction mixture was cooled to room temperature and filtered throughcelite pad. The pad was washed several times with DCM. The filtrate wasdried over sodium sulfate and concentrated. A crude material 134 wasused in the next step without further purification.

Aldehydes of formula (XX) may also be made according to theabove-outlined procedure where, although the absolute quantities ofstarting materials, reactants and reagents used therein may deviate fromthose in the above-outlined procedure, within any given step therelative molar quantities of starting materials, reactants and reagentsas well as concentrations are consistent with those stipulated in theabove-outlined procedure.

Method I (Synthesis of Compounds of the Invention where One of R¹ or R²is Cl):

In certain cases where one of R¹ or R² in a compound of the presentinvention is Cl and the other is an unsubstituted or substituted phenylring, the compounds of the present invention may be made via thefollowing process.

Chloroimidazoles of formula (LXI) can be made from via cyclisation ofamides of formula (LX) preferably using standard conditions for suchtransformations, for example reaction with PPh₃, CCl₄ and a base, forexample an organic base such as DIPEA. Amides of formula (LX) can bemade from acids of formula (LIX) preferably via standard amide couplingconditions with the appropriate aminoacetonitrile, for example using anamide coupling agent such as CDI in a suitable solvent such as CH₂Cl₂.

Carboxylic acids of formula (LIX) are generally commercially availablefrom supplier such as, for example, Enamine (Kiev, Ukraine) orSigma-Aldrich (St. Louis, Mo., USA) but in instances where carboxylicacids of formula (LIX) are not commercially available they may be madeby at least one of a number of standard methods known to the personskilled in the art such as, for example, hydrolysis of the correspondingnitrile or ester, or oxidation of the corresponding aldehyde, thesynthesis for which is outlined in numerous locations throughout thepresent document including, for example, in Method H.

Aminoacetonitriles are generally commercially available from suppliersuch as, for example, Enamine (Kiev, Ukraine) or Sigma-Aldrich (St.Louis, Mo., USA) but in instances where aminoacetonitriles are notcommercially available they may be made by at least one of a number ofstandard methods known to the person skilled in the art such as, forexample, the method outlined in U.S. Pat. No. 5,332,825.

Step K:

A round-bottomed flask was charged with solution of compound 135 (272mg, 1.0 mmol) in THF (20 mL). To a stirred solution a CDI(1,1′-Carbonyldiimidazole) (177 mg, 1.1 mmol) was added in one portion,and stirring was continued for 1 h. Then 2-amino-2-phenylacetonitrile(commercially available from, inter alia, Bepharm and Ukrorgsyntez Ltd.)(132 mg, 1.0 mmol) was added in one portion, and stirring was continuedfor 24 h. Then solution was concentrated, a residue was suspended in DCM(25 mL). The suspension was washed with water, and organic phase wasseparated and dried over sodium sulfate. The volatiles were evaporatedto afford of the target material 136 in 159 mg (0.41 mmol, 41%) yield.

Step L:

A round-bottomed flask was charged with compound 136 from step K (159mg, 0.42 mmol), PPh₃ (275 mg, 1.05 mmol), DIPEA (173 mg, 1.34 mmol), andCCl₄. The reaction mixture was refluxed for 12 h, cooled to r.t, andwashed with water (2×50 mL). The organic layer was dried over sodiumsulfate and concentrated. A crude residue (100 mg) was purified bycolumn chromatography on silica gel (hexane with MTBE). The yield ofcompound 137 was 25 mg.

Examples of compounds of the invention which have been made using MethodI include

Compound 64 below was synthesized in from5-(2-(trifluoromethoxy)phenyl)furan-2-carboxylic acid (commerciallyavailable from Enamine (Kiev, Ukraine)) and 2-amino-2-phenylacetonitrile(commercially available from Enamine (Kiev, Ukraine)) using 2.0 mmol ofthe acid SM using the conditions outlined above.

Compound 65 below was synthesized in 9% yield5-(2-(trifluoromethyl)phenyl)furan-2-carboxylic acid (commerciallyavailable from Enamine (Kiev, Ukraine)) and 2-amino-2-phenylacetonitrile(commercially available from, inter alia, Bepharm (Shanghai, China andUkrorgsyntez Ltd (Kiev, Ukraine)) using 2.0 mmol of the acid SM usingthe conditions outlined above.

Biological Materials

The following bacterial strains were obtained from the American TypeCulture Collection (Manassas, Va.; USA): Enterococcus faecium (straindesignation AGR15, ATCCBAA-2127™), Streptococcus pneumoniae (Chester,ATCC49619™), Bacillus subtilis (Marburg strain, ATCC6051™), Enterococcusfaecalis (ATCC29212™), Staphylococcus epidermidis (PCI 1200,ATCC12228™), Mycobacterium smegmatis (mc(2)155, ATCC®700084™),vancomycin-resistant Enterococcus faecium (ATCC51559),vancomycin-resistant Enterococcus faecalis (ATCC51575), and thepenicillin-, erythromycin- and tetracycline-resistant Streptococcuspneumoniae (ATCC 700677), called herein ARSP. The methicillin-resistantStaphylococcus aureus MRSA (COL) strain (Gill S R et al. 2005, JBacteriol. 187(7):2426-38) is available at the Culture Collection ofSwitzerland (CCOS 461) and so is the methicillin-sensitiveStaphylococcus aureus MSSA (Newman) strain (Duthie E S et al. 1952, J.Gen. Microbiol. 695-107) as CCOS 199. The Escherichia coli (E. coli)TolC mutant strain ΔtoIC (K12 b3035 TolC; JW5503) was obtained from GEHealthcare Dharmacon. Bacterial strains were stored in media (see below)supplemented with 50% glycerol at −80° C.

The antibiotic-resistant strains linezolid-resistant Staphylococcusaureus, vancomycin-resistant Staphylococcus aureus, daptomycin-resistantStaphylococcus aureus, moenomycin-resistant Staphylococcus aureus, andplatensimycin-resistant Staphylococcus aureus were produced byserial-passage mutagenesis of the methicillin-resistant Staphylococcusaureus (MRSA, COL) in the presence of the relevant antibiotic using apublished method (Friedman L et al. 2006, Antimicrob. Agents Chemother.50:2137-2145). Specifically, standard MIC assays (see below) wereperformed for 24 h at 37° C. on day 1 (generation I) with antibiotics atconcentrations as follows: linezolid: 0 μM-29.6 μM; vancomycin: 0 μM-6.7μM; daptomycin: 0 μM-6.2 μM; platensimycin: 0 μM-22.6 μM, and platencin0 μM-23.5 μM). The bacteria from cultures with the highest antibioticsconcentrations that were still able to support staphylococcal growthwere subsequently used as the inoculum (diluted 1:1000 in fresh trypticsoy broth (TSB; details below)) for a subsequent series of incubation at37° C. under MIC-assay conditions (generation II; passage I) in TSBsupplemented again with increasing concentrations of referencecompounds. Serially repeated selection procedures were done in thismanner until a stable antibiotic-resistant Staphylococcus aureus mutantwas generated. The levels of resistance were determined by the brothmicrodilution minimal inhibitory concentration (MIC) Assay (detailedbelow).

Thus for linezolid 25 passages were needed to obtain a strain resistantto 7.5 μg/ml of linezolid (MIC 7.5 μg/ml for the resistant strain); forvancomycin 25 passages (MIC of 20 μg/ml for the resistant strain); fordaptomycin 15 passages (MIC >50 μg/ml for the resistant strain); forplatensimycin 2 passages (MIC >10 μg/ml for the resistant strain).Resistant clones were taken from the relevant microtiter platepositions, and streaked out to obtain single colonies on TSB agar. Thelevels of resistance were then confirmed by a standard MIC procedure(detailed below).

Strains of MRSA (COL) resistant to triclosan or moenomycin weregenerated on plates of TSB-agar incubated at 37° C. with 4 μg/ml oftriclosan or 0.3 μg/ml of moenomycin. This resulted in resistant strainswith MIC values of >20 μg/ml for triclosan and of >10 μg/ml formoenomycin. Strains were stored in TSB medium supplemented with 50%glycerol at −80° C.

The bacterial strains Staphylococcus aureus MRSA (COL), theantibiotics-resistant MRSA strains (with resistance against linezolid,daptomycin, triclosan, vancomycin, platensimcyin, or moenomycin),Staphylococcus aureus MSSA (Newman), Staphylococcus epidermidis,Bacillus subtilis, Enterococcus faecalis, and Enterococcus faecium weregrown and tested in Mueller-Hinton Broth (Becton Dickinson Biosciences;#211443) or tryptic soy broth medium (Becton Dickinson Biosciences;#211822. For testing of daptomycin, the medium was supplemented with 75mg/L of CaCl₂.2H₂O. Streptococcus pneumoniae was grown in brain-heartbroth (Merck, #1.10493) in a 5% CO₂ atmosphere. Mycobacterium smegmatiswas grown in Middlebrook 7H9 broth (Becton Dickinson Biosciences,#271310) in a 5% CO₂ atmosphere at 37° C. E. coli ΔtoIC was grown in instandard nutrient-rich Miller's Luria broth medium (Sigma-Aldrich;L3522).

Human hepatocytes (HepaRG™ cells) were obtained from Life Technologies,and were cultivated in William's E Medium (Gibco, Life Technologies;A12176-01) supplemented with 1× GlutaMAX™ plus 1× HepaRG™ GeneralPurpose Medium Supplement in 25 cm² or 75 cm² flasks (TPP, Trasadingen,Switzerland) at 37° C. at 5% CO₂. Human keratinocytes (HaCaT cells;Boukamp P et al., 1988, J Cell Biol 106:761-771) were propagated inEpilife Medium (Gibco, Life Technologies; MEPICF) combined with CaCl2,1×-growth-supplement containing penicillin and streptomycin (Gibco, LifeTechnologies). For sub-culturing, cells were split at a ratio of 1:4 to1:8. For cryopreservation, cells were frozen down in 10% DMSO in liquidnitrogen.

Sources of the commercially available antibiotic substances are:linezolid (Santa Cruz Biotechnology, Inc.; sc-207827), triclosan(Calbiochem; 647950), vancomycin (Sigma-Aldrich®; 861987); moenomycin(Santa Cruz; sc-362031), daptomycin (Sigma-Aldrich®; D2446), andplatensimycin (Calbiochem #528244).

Biological Tests

The broth microdilution Minimal Inhibitory Concentration (MIC) Assay wasused to determine antibacterial activities of compounds. Compounds usedfor biological tests were stored at −20° C. as powders. Stock solutions(10-50 mM) of these test compounds were prepared in 100% DMSO (D2438,Sigma-Aldrich (St. Louis, Mo., USA)), and stored at −20° C. Brothmicrodilution MIC testing was performed according to the protocolslisted in NCCLS M7-A6 (National Committee for Clinical LaboratoryStandards, NCCLS. 2003: Methods for dilution antimicrobialsusceptibility tests for bacteria that grow aerobically. Approvedstandard, 6th ed. NCCLS document M7-A6, NCCLS, Wayne, Pa., USA) withadaptations as described below. Briefly, eleven two-fold dilutions ofthe compounds under study in the range from 0 μM to 200 μM (i.e., 0 μM,0.4 μM, 0.78 μM, 1.56 μM, 3.12 μM, 6.25 μM, 12.5 μM, 25 μM, 50 μM, 100μM, 200 μM) were prepared as 100× concentrated stocks dissolved in 100%sterile DMSO. Of each, 1 μl was added to a single well of a sterile96-well microtiter plate (#163320, ThermoScientific) and then filled-upwith 100 μl of medium containing approximately 10⁵ bacteria(corresponding to a 1:1000 dilution of a stationary overnight culture infresh medium). MRSA-COL, MSSA-Newman, S. epidermidis, B. subtilis, E.faecalis, and E. faecium were propagated in TSB broth (all at 37° C.).S. pneumonia was incubated in brain-heart broth a 37° C. with 5% CO₂,and E. coli ΔtoIC in nutrient-rich Miller's Luria broth. For M.smegmatis, MIC assays were performed in a twofold scaled-up volume inorder to account for eventual evaporation of Middlebrook 7H9 broth giventhe prolonged incubation time of 3 days at 37° C. in a 5% CO₂ incubator.In all experiments, the DMSO concentration was kept at 1%. Followingrotational incubation at 200 rpm for 24 hours, plates were assayedvisually and the optical density (OD600), which measures bacterial cellgrowth and proliferation, measured via a multimode reader (GloMax® MultiDetection Platform, Promega Corporation, Madison, Wis., USA). Growth wasdefined as turbidity achieving a minimum OD600 of <0.1; MIC values (inμg/ml) are concentrations preventing bacterial growth 100% (MIC100)unless indicated otherwise.

MIC values thus obtained for reference antibiotics were consistent withthe values published by the British Society for AntimicrobialChemotherapy (as published in BSAC Methods for AntimicrobialSusceptibility Testing (Version 12 May 2013, available athttp://bsac.org.uk/wp-content/uploads/2012/02/Version-12 Apr.2013_final.pdf.) and in the scientific literature.

Combinations of antibacterial compounds were assessed for cooperativeinteractions in checkerboard broth micro-dilution setups whereintwo-dimensional titration matrices enable the calculation of so-calledfractional inhibitory concentration (FIC) indexes, termed FICi (Odds F.C. 2003: Synergy, antagonism, and what the chequerboard puts betweenthem. Journal of Antimicrobial Chemotherapy 52:1; Drago, L. et al. 2007:In vitro evaluation of antibiotics' combinations for empirical therapyof suspected methicillin resistant Staphylococcus aureus severerespiratory infections. BMC Infectious Diseases 7:111). To this end, thewells of a 96-well flat-bottom polystyrene microtiter plate wereinoculated with 10⁶ cfu/ml S. aureus strain MRSA-COL in standard trypticsoy broth (TSB) culture medium, and challenged with serially-dilutedcompounds at concentrations bracketing the pre-determined MIC values. A90° angle rotated pipetting-scheme was used to provide all possible dosecombinations of two compounds under study. Specifically, compounds inthe range of 0, 0.78, 1.56, 3.12, 6.25, 12.5, 25, 50, 100, and 200 μM(vertical columns) were examined for possible potentiating effects onhorizontal rows of arrayed platensimycin concentrations. Optical density(OD₆₀₀) was then measured within technical replicates after a 24-hourincubation period at 37° C. The FIC was determined for each individualsubstance by dividing the MIC-value of the compound when used incombination by the MIC when used alone, i.e.,FIC_(A)=MIC_(A in combination)/MIC_(A alone) andFIC_(B)=MIC_(B in combination)/MIC_(B alone). FICi was then quantifiedas the sum of the two FIC values for each drug present in the well; thatis, FICi=FIC_(A)+FIC_(B). Arbitrary thresholds of ≤0.5; >0.5 to ≤1.0; >1to ≤4, and >4.0 were lastly used to score synergistic, additive(combined effect equal to the sum of the individual components),indifferent (neutral) or antagonistic (adverse interaction) effectswithin paired compound combinations, respectively.

Human cytotoxicity assays in vitro were done as described in “GuidanceDocument on Using In Vitro Data to Estimate In Vivo Starting Doses forAcute Toxicity Based on Recommendations” available atwww.epa.gov/hpv/pubs/general/nih2001b.pdf. Briefly, human hepatocytes orhuman keratinocytes (HaCaTs) were seeded into sterile blackclear-bottomed polystyrene Corning® CellBind® 96-well plates at adensity of 20,000 cells/well after calculating cell numbers fromtrypsinized samples in a classical Neubauer Improved haemocytometer. Thecells were grown for 24 h at 37° C. in a 5% CO₂ atmosphere in Epilifemedium (keratinocytes) or William's E medium (hepatocytes). After a 24 hrecovery period, media were removed from the wells by aspiration. Thecells were then immediately exposed to the respective test compounds orreference antibiotics (prepared in advance in 100 μl of the same media)for 24 h 37° C. with 5% CO₂. The concentration range tested extendedfrom 0.1 μM to 100 μM (0.1 μM, 1 μM, 5 μM, 10 μM, 25 μM, 50 μM, 75 μM,100 μM) and was formulated as a 100× concentrated stock each, resultingin a final constant DMSO concentration of 1% per 100 μl sample volume.Test series were performed in triplicates each, and additionallyincluded a vehicle reference (DMSO only) plus a further internal controlfor evaluating overall assay performance. Also, cells were visuallyexamined under a light microscope for any morphological abnormalitiesrelative to the untreated cells. Subsequently, cell viability asindicator of potential cytotoxicity was measured by applying theCellTiter-Glo® luminescent cell proliferation assay (G755A, Promega,Madison, Wis., USA). This method permits the determination of the numberof viable cells in culture based on quantitation of the ATP present,which denotes the presence of metabolically active cells (Crouch, S. P.et al. 1993, J. Immunol. Methods 160, 81-8). To this end, 100 μl (equalto the volume of culture medium) of the kit-provided CellTiter-Glo®reagent (reconstituted by transferring the thawed CellTiter-Glo® bufferto the lyophilized enzyme and substrate mixture) was directly added toeach well with a repetitive dispensing pipette. Contents were then mixedfor 2 min at room temperature on an orbital minishaker (IKA® MS3digital) at 450 rpm to induce efficient cell lysis, and then furtherincubated for 10 min at room temperature for stabilization of theresultant luminescent signal. Luminescence was recorded using acompatible multimode reader (GloMax® Multi Detection Platform, PromegaCorporation, Madison, Wis., USA) with its embedded, presetCellTiter-Glo® parameters (integration time of 0.5 sec). Output valueswere expressed as percent cell viability compared to vehicle (DMSO)control, and EC50 values calculated from the dose-response curves vianonlinear regression (Graphpad Prism Software Inc., La Jolla, Calif.,USA).

Biological Results Example A

Representative compounds of the present invention, their syntheticroutes and analytical characterizations are listed in Table AA. Thesecompounds were tested for antibacterial activity against Streptococcuspneumoniae, Staphylococcus aureus MSSA (Newman) and Staphylococcusaureus MRSA (COL) according to the MIC procedure described in BiologicalTests. The results are also listed in Table AA. With respect tostreptococci (e.g. Streptococcus pneumonia), “4” indicates that thecompound has an MIC of 1 μg/ml or less for preventing streptococcalgrowth 100% (MIC100). With respect to staphylococci (e.g. Staphylococcusaureus MSSA (Newman) and Staphylococcus aureus MRSA (COL)), “4”indicates that the compound has an MIC of ≥1 μg/ml to 3 μg/ml forpreventing staphylococcal growth 100% (MIC100). For streptococci, thenotation “3” indicates that the compound has an MIC100 of 2-5 μg/ml,whilst for staphylococci the notation “3” indicates that the compoundhas an MIC100 of 3-10 μg/ml. For streptococci, the notation “2”indicates that the compound has an MIC100 of 6-10 μg/ml, whilst forstaphylococci the notation “2” indicates that the compound has an MIC100of 11-201 μg/ml. For streptococci, the notation “1” indicates that thecompound has an MIC100 of 11-201 μg/ml or an MIC50 of <10 μg/ml, whilstfor staphylococci the notation “1” indicates that the compound has anMIC100 of 20-50 μg/ml or an MIC50 of <10 μg/ml. The compounds showactivity against Streptococcus pneumoniae or Staphylococcus aureus, orboth. “Inactive” means that no antibacterial activities were observed ata concentration of 200 μg/ml.

Example B

Compounds represented in Table AA were tested for cytotoxicity in vitroagainst human hepatocytes and human keratinocytes according to thecytotoxicity assay described in Biological Tests. A hepatocytecytotoxicity score of 4 was assigned to compounds inhibiting cellviability 50% or more at concentrations of 10 μM or less. The hepatocytecytotoxicity score of 3 was assigned to compounds causing at least 80%inhibition of viability at 25 μM, of 2 to compounds showing toxicity at25 μM, but causing less than 20% inhibition of viability, of 1 tocompounds not causing a loss of viability at concentrations between 25and 50 μM, and of 0 to compounds without signs of cell viability loss atconcentrations of 50 μM or higher. A keratinocyte cytotoxicity score of4 was assigned to compounds inhibiting cell viability 50% or more atconcentrations of 5 μM or less. The keratinocytes cytotoxicity score 3was used for compounds causing more than 50% inhibition of cellviability at 10 μM; 2 for compounds causing >50% inhibition of cellviability at 25 μM; 1 for compounds causing less than 50% inhibition ofcell viability at 50 μM, and 0 for compounds not causing loss of cellviability at concentrations of 50 μM or higher. Compounds withcytotoxicity scores of less than 4 in either keratinocytes orhepatocytes, or both, are preferred, and were tested against a panel ofbacteria, including bacterial strains with resistance to antibioticsobtained as described in Biological Materials. Results are shown inTable BB. With respect to streptococci, “4” indicates that the compoundhas an MIC of 1 μg/ml or less for preventing streptococcal growth 100%(MIC100). With respect to the other bacteria, “4” indicates that thecompound has an MIC of ≥1 μg/ml to 3 μg/ml for preventing bacterialgrowth 100% (MIC100). For streptococci, the notation “3” indicates thatthe compound has an MIC100 of 2-5 μg/ml, whilst for the other bacteriathe notation “3” indicates that the compound has an MIC100 of 3-10μg/ml. For streptococci, the notation “2” indicates that the compoundhas an MIC100 of 6-10 μg/ml, whilst for the other bacteria the notation“2” indicates that the compound has an MIC100 of 11-201 μg/ml. Forstreptococci, the notation “1” indicates that the compound has an MIC100of 11-201 μg/ml or an MIC50 of <10 μg/ml, whilst for other the bacteriathe notation “1” indicates that the compound has an MIC100 of 20-50μg/ml or an MIC50 of <10 μg/ml.

In Table BB, when in a cell of the table a label of a particularbacterial species, e.g. MSSA as the label for multi-drug resistantStaphylococcus aureus MSSA, does not fit onto one line of the cell, andthus the letters MSSA are divided over two or more lines of the cell,the letters on one line of a given cell are not to be read in isolationbut instead in combination with the letters on the remaining lines ofthe cell. A cell thus displaying “MS” on one line and “SA” on a secondline of the same cell of the table is to be understood to refer to asingle bacterial species, in this case “MSSA”, and is in no way relatedto, for example, the bacteria labeled simply “MS”, i.e. Mycobacteriumsmegmatis.

In one aspect, the invention thus provides a method for inhibiting thegrowth of microorganisms, preferably bacteria, comprising contactingsaid organisms with a compound of the invention, preferably a compoundrepresented in Table BB, under conditions permitting entry of thecompound into said microorganism. This method involves contacting amicrobial cell with a therapeutically-effective amount of compound(s) ofthe invention, preferably of compounds represented in Table BB, in vivoor in vitro.

In some embodiments, the invention provides a method for treating aninfection, especially infections caused by gram-positive bacteria, in asubject with a therapeutically-effective amount of a compound of theinvention.

In a preferred embodiment, the bacterial infection is caused bygram-positive bacteria, e.g. selected from staphylococci, streptococci,enterococci, bacilli, and mycobacteria.

In a preferred embodiment, the bacterial infection is caused bygram-positive bacteria resistant against beta-lactam antibiotics such asmethicillin. In another preferred embodiment the bacterial infection iscaused by gram-positive bacteria resistant against other or additionalantibiotics such as daptomycin, vancomycin, linezolid, triclosan,moenomycin or platensimycin. In a preferred embodiment the infection iscaused by staphylococci or streptococci resistant to beta-lactamantibiotics. In another preferred embodiment the infection is caused bymulti-drug resistant bacteria, such as staphylococci resistant tobeta-lactam antibiotics and at least one other antibiotic substance,e.g. selected from daptomycin, vancomycin, linezolid, triclosan,moenomycin or platensimycin. In a further preferred embodiment theinfection is caused by enterococci resistant to vancomycin. In anotherpreferred embodiment the infection is caused by multi-drug resistantstreptococci, such as streptococci resistant against penicillins anderythromycin and/or tetracyclines.

In a further aspect the present invention provides a compound for use inthe preparation of a medicament for the treatment of microbial diseases,for example of diseases caused by bacteria, e.g. selected fromstaphylococci, streptococci, enterococci, bacilli, and mycobacteria. Ina further aspect the present invention provides a compound for use inthe preparation of a medicament for the treatment of diseases caused bybacteria resistant to antibiotics, such as beta-lactam antibiotics,daptomycin, vancomycin, linezolid, triclosan, moenomycin orplatensimycin, or resistant against beta-lactam antibiotics,erythromycin or tetracyclines, and in addition to daptomycin,vancomycin, linezolid, triclosan, moenomycin or platensimycin.

The compounds of the invention may thus be used as antibiotics. Theinvention also provides a method for the treatment of additionaldiseases or conditions in which microbes play a role, for example intreatments of infections in immune-compromised hosts, including forexample subjects infected with HIV or having AIDS, said methodcomprising a step of administering to a subject in need thereof aneffective amount of a compound of the invention, said subject being amammal, in particular a human.

The invention thus also provides a method for the treatment of microbialinfection, said method comprising a step of administering to a subjectin need thereof an effective amount of a compound of the invention, saidsubject being a mammal, in particular a human.

The present invention provides a method of treating or preventing abacterial infection in a subject, or a disorder related to a bacterialinfection in a subject, comprising the step of administering atherapeutically-effective amount of a pharmaceutical compositioncomprising a compound of the invention to a subject in need thereof. Thesubject is preferably selected from the group consisting of a human, ananimal, a cell culture, and a plant, more preferably from the groupconsisting of a human and an animal, and is most preferably a human. Thebacterial infection may be caused by a Gram-positive bacterial species.The bacterial species may be a bacterial species which exhibitsresistance to antibiotics. In some embodiments, the bacterial species isselected from the group consisting of Streptococci, Staphylococci,Bacilli, Enterococci and Mycobacteria. In such cases, Streptococci maybe Streptococcus pneumonia, Staphylococci may be Staphylococcus aureus,Staphylococci may be methicillin-resistant Staphylococcus aureus,Staphylococci may be Staphylococcus epidermidis, Bacilli may be Bacillussubtilis, Enterococci may be Enterococcus faecium, Enterococci may beEnterococcus faecalis, and Mycobacteria may be Mycobacterium smegmatis.In some embodiments, the compounds of the invention are used in thetreatment of microbial infections caused by one or more of theseorganisms. Bacterial species which exhibit resistance to antibiotics mayinclude, for example, daptomycin-resistant Staphylococcus aureus,daptomycin-resistant Enterococcus faecium, daptomycin-resistantEnterococcus faecalis, and methicillin-resistant Staphylococcus aureus.Antibiotics to which the bacterial species may exhibit resistanceinclude, for example, vancomycin, methicillin, glycopeptide antibiotics,penicillin, and daptomycin. In some embodiments, the bacterial infectionor disorder related to a bacterial infection may involve a mixture ofbacterial species, optionally a mixture of bacterial species comprisingat least one bacterial species which exhibits resistant to antibiotics,said species optionally being at least one of the antibiotic-resistantspecies listed hereinabove and/or optionally exhibiting resistance toone of the antibiotics listed hereinabove. The bacterial species may bean antibiotic-resistant Gram-positive bacterial species, including, forexample, multidrug-resistant streptococci, multidrug-resistantstaphylococci, or multidrug-resistant enterococci, or a mixture ofbacterial species comprising at least one of these antibiotic-resistantbacterial species.

In the present invention, the antibiotic-resistant bacteria againstwhich the compounds of the invention show activity do not exhibitresistance to the compounds and/or compositions of the invention.

As used throughout herein, the term “microbial” is to be understood topreferably mean “bacterial”. Accordingly, as used throughout herein, theterm “antimicrobial” is to be understood to preferably mean“antibacterial”, and the term “microbial infection” is to be understoodto preferably mean “bacterial infection”. “Infections” describedthroughout herein are preferably “bacterial infections”.

The methods of the invention may further comprise the step ofco-administering more than one compound of the invention to a subject inneed thereof. This may be performed in one single dosage form or inseparate dosage forms for simultaneous, separate or sequential use inthe prevention or treatment of bacterial infections. The methods of theinvention my further comprise the step of co-administering anantimicrobial agent other than a compound of the invention to a subjectin need thereof. This may be performed in one single dosage form or inseparate dosage forms for simultaneous, separate or sequential use inthe prevention or treatment of bacterial infections.

A further aspect of the invention thus relates to methods forpreventing, inhibiting, or stopping the growth of bacteria on suchsurfaces involving the step of applying at least one compound of theinvention directly or indirectly and in either pure form or in analternative form, such as those disclosed herein, to said surface.Compounds of the invention may thus be formulated as an antiseptic,disinfectant or antimicrobial agent and used, for example, in one ormore of the methods disclosed herein.

In some embodiments, a compound of the invention is provided for use inthe treatment of microbial infection and/or a disorder, affliction orillness caused at least in part by microbial infection, in particularwhere said microbial infection is a bacterial infection and especially abacterial infection caused at least in part by one or more Gram-positivebacterial species, especially wherein said one or more Gram-positivebacterial species include Gram-positive bacterial species resistant toexisting antibiotics, including in particular multidrug-resistantstreptococci, multidrug-resistant staphylococci, or multidrug-resistantenterococci. Said microbial or bacterial infections may include mixedinfections involving both Gram-positive bacterial species resistant toand Gram-positive bacterial species sensitive to existing antibioticsand/or a mixture of bacterial species comprising at least one bacterialspecies which exhibits resistance to existing antibiotics. In some ofthese embodiments, said existing antibiotics are preferably selectedfrom one or more members of the group of antibiotics consisting ofcephalosporins, quinolones, macrolides, vancomycin, daptomycin,linezolid, moenomycin, platensimycin, and beta-lactam antibioticsincluding penicillins.

The terms “existing antibiotics” and “existing therapies” may beunderstood to refer to agents and therapies which were known in the arton 4 Dec. 2014 to have antibiotic activity and/or to be applicableto/used in the treatment of microbial infection and/or a disorder,affliction or illness caused at least in part by microbial infection, inparticular where said microbial infection is a bacterial infection andespecially a bacterial infection caused at least in part by one or moreGram-positive bacterial species. They may be understood to refer inparticular to antibiotic agents or therapies which had been authorizedand/or marketed in a country or region at or before that time or whichwere known in the art at that time to be in clinical development,pre-clinical development or pre-clinical research. Antibiotics may beunderstood to constitute a therapy for microbial infections, disorders,afflictions and illnesses in this sense. Antibiotic activity in thissense may be understood to be as defined elsewhere herein.

It has surprisingly also been found that the compounds of the inventionare also effective in and thus may find use in preventing, inhibiting,or stopping the growth of bacteria on surfaces. Such surfaces mayconstitute hard surfaces such as, for example, floors, worktops,bathroom surfaces, glass surfaces, crockery, cutlery, pots, pans,devices such as household devices or medical devices including contactlenses, or soft surfaces, such as, for example, skin, hair, clothing,contact lenses and the like. The compounds of the invention may thus beformulated and used as antiseptics, disinfectants, etc and/or used ascomponents, additives or preservatives for medical/surgical devices,disinfectants, soaps, shampoos, hand washes, denitrifiers, householdcleaning formulations, detergents for laundry and dishes, in wash andtreatment solutions for topical use, instruments and devices includingcontact lenses, and in other disinfecting and antibacterialapplications.

A further embodiment of the invention thus relates to the use of thecompounds of the invention in preventing, inhibiting, or stopping thegrowth of bacteria on surfaces, said surfaces including both hardsurfaces such as floors, worktops, bathroom surfaces, glass surfaces,crockery, cutlery, pots, pans, surfaces of devices such as householddevices or medical devices including contact lenses, and soft surfacessuch as skin, hair, clothing, contact lenses and the like.

In one embodiment (E1), the present invention relates to a compoundcomprising or consisting of the structural moiety of formula (I) or apharmaceutically-acceptable salt of said compound, for use as amedicament

wherein(i) Y is C or N;(ii) R¹ and R² are independently selected from the group consisting of:H, —CH₃, C_(2to6)alkyl, C_(3to6)cycloalkyl, halogen, —(CH₂)_(n)N(CH₃)₂where n is an integer from 1 to 3, benzyl optionally substituted on thephenyl ring, heteroaryl, and aryl,with the proviso that at least one of R¹ or R² possesses 3 or morecarbon atoms;orR¹ and R² are connected to form a four-, five- or six-memberednon-aromatic carbocyclic ring thus providing a fused bicyclic moiety inwhich one or more of the carbon atoms of the ring comprising groups R¹and R² is optionally replaced by a heteroatom selected from O, N, or S,and where one or more of the atoms of the ring comprising groups R¹ andR² is optionally substituted with one or more substituents independentlyselected from the group consisting of —CH₃, C_(2to4)alkyl, halogen,hydroxyl, —OCH₃, —OC_(2to4)alkyl, ethynyl, —OCF₃, and —CF₃;

-   -   with the proviso for all of the above-mentioned alternatives        that when:        Y is N, R² represents a lone pair of electrons belonging to the        N atom; and        (iii) A is aryl or heteroaryl; and        (iv) B is aryl, heteroaryl, a bicyclic system comprising at        least one aromatic ring, or styryl.

A further embodiment (E2) relates to a compound for use as in embodiment(E1), wherein A is 5-membered heteroaryl.

A further embodiment (E3) relates to compound for use as in either ofembodiments (E1) or (E2), wherein A is selected from the groupconsisting of

where * is the point of connection to the correspondingly-labeled atomof B and ** is the point of connection to the correspondingly-labeledatom of

and wherein the aromatic ring of A is optionally substituted; and/orwherein B is selected from the group consisting of

where * is the point of connection to the correspondingly-labeled atomof A; and wherein B is optionally substituted.

A further embodiment (E4) relates to a compound for use according to anyof embodiments (E1) to (E3), wherein group A is selected from theformulae

and is preferably

wherein * and ** are as defined above.

A further embodiment (E5) relates to a compound for use according to anyof embodiments (E1) to (E4), wherein the aromatic ring of A issubstituted by one or more substituents independently selected from—CH₃, C_(2to4)alkyl, halogen, —OCH₃, and —OC_(2to4) alkyl, preferablysubstituted by one or more substituents independently selected from—CH₃, C_(2to4)alkyl, and halogen, most preferably by one or more —CH₃substituents.

A further embodiment (E6) relates to a compound for use according to anyof embodiments (E1) to (E5), wherein B is an unsubstituted phenyl ringor a substituted phenyl ring.

A further embodiment (E7) relates to a compound for use according to anyof embodiments (E1) to (E6), wherein B is a phenyl ring optionallysubstituted with one or more substituents independently selected fromthe group consisting of —CH₃, C_(2to4)alkyl, halogen, hydroxyl, —OCH₃,—OC_(2to4)alkyl, —CF₃, —OCF₃, —NH₂, —CH₂NH₂, —N(CH₃)₂, —NO₂, —CH₂OH,—CO₂CH₃, —CO₂C_(2to4)alkyl, —CO₂H, —N(alkyl)₂ where the two alkyl groupsare independently selected from —CH₃ or C_(2to4)alkyl, —NH(alkyl) wherethe alkyl group is selected from —CH₃ or C_(2to4)alkyl, 4-morpholinyl,1-piperidinyl, 4H-piperazinyl, 4-C_(1to4)alkyl-piperazinyl, and4-C_(3to6)cycloalkyl-piperazinyl, preferably independently selected fromthe group consisting of H, —CH₃, C_(2to4)alkyl, iso-propyl, tert-butyl,halogen wherein halogen is preferably F or Cl or Br, hydroxyl, —OCH₃,—CF₃, —OCF₃, —N(CH₃)₂, —NO₂, and 4-methylpiperazinyl, more preferablyindependently selected from the group consisting of H, —CH₃, —CH₂CH₃,iso-propyl, —N(CH₃)₂, halogen wherein halogen is preferably F or Cl orBr, —OCH₃, —CF₃, and —OCF₃.

A further embodiment (E8) relates to a compound for use according to anyof embodiments (E1) to (E5), wherein B is a ring other than anunsubstituted or substituted phenyl ring and B is substituted orunsubstituted.

A further embodiment (E9) relates to a compound for use according to anyof embodiments (E1) to (E5) or (E8), wherein B is a ring other than anunsubstituted or substituted phenyl ring and is optionally substitutedwith one or more substituents independently selected from the groupconsisting of —CH₃, C_(2to4)alkyl, halogen wherein halogen is preferablyF or Cl or Br, hydroxyl, —OCH₃, —OC_(2to4)alkyl, —CF₃, —OCF₃, —CO₂CH₃,—CO₂C_(2to4)alkyl, and —CO₂H, more preferably selected from the groupconsisting of —CH₃, —CF₃, —OCF₃ and halogen, wherein halogen ispreferably F or Cl or Br.

A further embodiment (E10) relates to a compound for use according toany of embodiments (E1) to (E9), wherein one of R¹ or R² is substitutedor unsubstituted phenyl.

A further embodiment (E11) relates to a compound for use according toany of embodiments (E1) to (E10), wherein one of R¹ or R² is phenylsubstituted with one or more substituents independently selected fromthe group consisting of —CH₃, C_(2to4)alkyl, halogen, hydroxyl, —OCH₃,—OC_(2to4)alkyl, ethynyl, —OCF₃, and —CF₃, more preferably with one ormore substituents independently selected from the group consisting of—CH₃, —CH₂CH₃, —OH, —CF₃, —OCF₃, ethynyl, and halogen, wherein halogenis preferably F or Cl or Br, most preferably with one or moresubstituents independently selected from the group consisting of —CH₃,—CH₂CH₃, —CF₃, —OCF₃, ethynyl, and halogen, wherein halogen ispreferably F or Cl or Br.

A further embodiment (E12) relates to a compound for use according toany of embodiments (E1) to (E11), wherein one of R¹ or R² is H, orhalogen in particular where halogen is chlorine, or most preferably—CH₃.

A further embodiment (E13) relates to a compound for use according toany of embodiments (E1) to (E12), wherein Y is C.

A further embodiment (E14) relates to a compound as defined in any ofembodiments (E1) to (E13) for use in the treatment of microbialinfection and/or a disorder, affliction or illness caused at least inpart by microbial infection, in particular where said microbialinfection is a bacterial infection and especially a bacterial infectioncaused at least in part by one or more Gram-positive bacterial species,especially wherein said one or more Gram-positive bacterial speciesinclude Gram-positive bacterial species resistant to existingantibiotics, including in particular multidrug-resistant streptococci,multidrug-resistant staphylococci, or multidrug-resistant enterococci,wherein said microbial infections may include mixed infections involvingboth Gram-positive bacterial species resistant to and Gram-positivebacterial species sensitive to existing antibiotics and/or a mixture ofbacterial species comprising at least one bacterial species whichexhibits resistance to existing therapies; and wherein said existingantibiotics are preferably selected from one or more members of thegroup of antibiotics consisting of cephalosporins, quinolones,macrolides, vancomycin, daptomycin, linezolid, moenomycin,platensimycin, and beta-lactam antibiotics including penicillins.

A further embodiment (E15) relates to a compound as defined in any ofembodiments (E1) to (E14) for use as an antibiotic in the treatment ofbacterial infection and/or a disorder, affliction or illness caused atleast in part by bacterial infection, said bacterial infection beingpreferably selected from one or more infections and infectious diseasesfrom the list of including respiratory tract infections, complicatedskin and soft tissue infections, complicated intra-abdominal infections,community acquired pneumonia, hospital-acquired pneumonia,ventilator-associated pneumonia, urinary tract infections, bacterialmeningitis, infective endocarditis, sepsis, osteomyelitis, septicarthritis, septicemia, anthrax, osteomyelitis, tuberculosis, leprosy,necrotizing fasciitis, scarlet fever, rheumatic fever, postpartum fever,and streptococcal toxic shock syndrome, and additional nosocomialinfections, for example infections caused from the use of intravascularcatheters.

A further embodiment (E16) relates to a pharmaceutical compositioncomprising the compound according to any one of embodiments (E1) to(E15) and a pharmaceutically acceptable carrier.

TABLE AA Compounds of the invention, synthesis, characterization, andantibacterial properties Antibacterial activity Staphylo- Staphylo-Strepto- coccus coccus Synthetic Analytics coccus aureus aureus CompoundNumber Structure route (yield) NMR LC/MS pneumoniae (MSSA) (MRSA) 63

A (53%) Procedure 1, RT = 2.91 min. Purity 97%. Electrospray positiveion mode: m/z 371 (M + H)+. 3 3 3 75

A (34%) Procedure 1, RT = 2.79 min. Purity 95%; Electrospray positiveion mode: m/z 355 (M + H)+. 3 2 18

A (66%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (3H, s, CH₃), 6.99 (1H, d, J =3.2 Hz, furan), 7.03 (1H, d, J = 3.2 Hz, furan), 7.28 (1H, m,OCF₃-phenyl), 7.45 (5H, m, phenyl), 7.70 (2H, m, OCF₃-phenyl), 8.22 (1H,d, J = 6.8 Hz, OCF₃-phenyl) Procedure 1, RT = 3.06 min. Purity 92%.Electrospray positive ion mode: m/z 385 (M + H)+. 3 4 3 17

A (59%) ¹H NMR (400 MHz, acetone-d₆): δ 2.52 (3H, s, CH₃), 6.91 (1H, d,J = 3.2 Hz, furan), 7.01 (1H, d, J = 3.2 Hz, furan), 7.26 (1H, m,CF₃-phenyl), 7.42 (2H, m, phenyl), 7.60 (1H, m, CF₃-phenyl), 7.77 (3H,m, phenyl), 7.87 (1H, d, J = 8.0 Hz, CF₃-phenyl) 7.98 (1H, d, J = 8.0Hz, CF₃-phenyl) Procedure 1, RT = 2.91 min. Purity 99%. Electrospraypositive ion mode: m/z 369 (M + H)+. 3 3 4 70

Method A followed by introduction of the CH₂N(CH₃)₂ group as describedin Examples section (70%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.27 (6H, s, 2 ×CH₃), 3.60 (2H, s, CH₂), 6.92 (1H, d, J = 3.6 Hz, furan), 7.06 (1H, d, J= 3.6 Hz, furan), 7.28 (1H, m, phenyl), 7.41 (2H, m, phenyl), 7.60 (1H,m, CF₃-phenyl), 7.77 (1H, m, CF₃-phenyl), 7.87 (2H, m, phenyl), 7.91(1H, d, J = 8.0 Hz, CF₃- phenyl), 7.99 (1H, d, J = 8.0 Hz, CF₃- phenyl)Procedure 1, RT = 2.80 min. Purity 97%. Electrospray positive ion mode:m/z 412 (M + H)+. 3 1 1 76

A (69%) Procedure 1, RT = 2.15 min. Purity 100%. Electrospray positiveion mode: m/z 401 (M + H)+. 3 3 4 77

A (63%) Procedure 1, RT = 2.08 min. Purity 96%. Electrospray positiveion mode: m/z 335 (M + H)+. 3 3 3 78

B (68%) Procedure 1, RT = 2.12 min. Purity 92%. Electrospray positiveion mode: m/z 349 (M + H)+. 1 23

A (70%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.49 (3H, s, CH₃), 6.98 (1H, d, J =3.2 Hz, furan), 7.02 (1H, d, J = 3.2 Hz, furan), 7.27 (2H, m, F-phenyl),7.50 (2H, m, OCF₃-phenyl), 7.58 (1H, m, OCF₃-phenyl), 7.73 (2H, m, F-phenyl), 8.21 (1H, d, J = 8.0 Hz, OCF₃-phenyl) Procedure 1, RT = 3.04min. Purity 98%. Electrospray positive ion mode: m/z 403 (M + H)+. 4 3 438

A (59%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (3H, s, CH₃), 6.99 (1H, d, J =3.6 Hz, furan), 7.25 (2H, m, F-phenyl), 7.28 (1H, d, J = 3.6 Hz, furan),7.67 (2H, m, CF₃-phenyl), 7.71 (2H, m, F- phenyl), 8.17 (2H, m,CF₃-phenyl) Procedure 1, RT = 3.02 min. Purity 98%. Electrospraypositive ion mode: m/z 387 (M + H)+. 3 4 4 24

A (71%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (3H, s, CH₃), 6.98 (1H, d, J =3.6 Hz, furan), 7.03 (1H, d, J = 3.6 Hz, furan), 7.49 (2H, m,OCF₃-phenyl), 7.50 (2H, d, J = 8.4 Hz, Cl-phenyl), 7.57 (1H, m,OCF₃-phenyl), 7.74 (2H, d, J = 8.4 Hz, Cl-phenyl), 8.20 (1H, d, J = 7.6Hz, OCF₃-phenyl) Procedure 1, RT = 3.11 min. Purity 96%. Electrospraypositive ion mode: m/z 419 (M + H)+. 4 3 3 29

A (67%) Procedure 1, RT = 3.20 min. Purity 95%. Electrospray positiveion mode: m/z 463, 465 (M + H)+. 3 3 2 25

A (59%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.48 (3H, s, CH₃), 6.92 (1H, d, J =3.6 Hz, furan), 7.00 (1H, d, J = 3.6 Hz, furan), 7.59 (2H, d, J = 8.4Hz, Br- phenyl), 7.65 (1H, m, CF₃-phenyl), 7.68 (2H, d, J = 8.4 Hz,Br-phenyl), 7.82 (1H, m, CF₃-phenyl), 7.89 (1H, d, J = 7.6 Hz,CF₃-phenyl), 8.01 (1H, d, J = 8.0 Hz, CF₃-phenyl) Procedure 1, RT = 3.06min. Purity 98%. Electrospray positive ion mode: m/z 447, 449 (M + H)+.3 28

A (70%) Procedure 1, RT = 3.33 min. Purity 92%. Electrospray positiveion mode: m/z 397 (M + H)+. 3 1 1 26

A (49%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.55 (3H, s, CH₃), 7.04 (1H, d, J =3.6 Hz, furan), 7.24 (1H, d, J = 3.6 Hz, furan), 7.51 (2H, m,OCF₃-phenyl), 7.58 (1H, d, J = 7.2 Hz, OCF₃- phenyl), 7.84 (2H, d, J =8.0 Hz, CF₃- phenyl), 7.94 (2H, d, J = 8.0 Hz, CF₃- phenyl), 8.21 (1H,d, J = 7.2 Hz, OCF₃-phenyl) Procedure 1, RT = 3.14 min. Purity 95%.Electrospray positive ion mode: m/z 453 (M + H)+. 3 30

B (53%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.45 (3H, s, CH₃), 3.95 (2H, s,CH₂), 6.99 (1H, d, J = 3.6 Hz, furan), 7.17 (1H, d, J = 3.6 Hz, furan),7.23 (2H, d, J = 8.4 Hz, Br-phenyl), 7.40 (2H, m, OCF₃-phenyl), 7.46(2H, d, J = 8.4 Hz, Br-phenyl), 7.53 (1H, m, OCF₃- phenyl), 8.22 (1H, d,J = 8.0 Hz, OCF₃- phenyl) Procedure 1, RT = 3.14 min. Purity 100%.Electrospray positive ion mode: m/z 477, 479 (M + H)+. 4 3 3 4

A (85%) Procedure 1, RT = 2.98 min. Purity 100%. Electrospray positiveion mode: m/z 335 (M + H)+. 4 4 2 5

A (73) Procedure 1, RT = 2.96 min. Purity 100%. Electrospray positiveion mode: m/z 335 (M + H)+. 4 4 3 79

A (62%) Procedure 1, RT = 1.92 min. Purity 95%. Electrospray positiveion mode: m/z 347 (M + H)+. 3 80

A (69%) Procedure 1, RT = 2.01 min. Purity 95%. Electrospray positiveion mode: m/z 353 (M + H)+. 3 3 2 81

A (23%) Procedure 1, RT = 2.01 min. Purity 98%. Electrospray positiveion mode: m/z 337 (M + H)+. 1 82

A (82%) Procedure 1, RT = 2.86 min. Purity 100%. Electrospray positiveion mode: m/z 317 (M + H)+. 4 3 83

A (24%) Procedure 1, RT = 2.88 min. Purity 97%. Electrospray positiveion mode: m/z 365, 367 (M + H)+. 3 84

A (77%) Procedure 1, RT = 2.78 min. Purity 100%. Electrospray positiveion mode: m/z 317, 319 (M + H)+. 2 2 85

A (78%) Procedure 1, RT = 2.75 min. Purity 100%. Electrospray positiveion mode: m/z 323 (M + H)+. 4 4 86

A (46%) Procedure 1, RT = 2.67 min. Purity 100%. Electrospray positiveion mode: m/z 273 (M + H)+. 3 87

A (62%) Procedure 1, RT = 2.77 min. Purity 96%. Electrospray positiveion mode: m/z 333 (M + H)+. 4 4 88

A (79%) Procedure 1, RT = 2.87 min. Purity 98%. Electrospray positiveion mode: m/z 349 (M + H)+. 4 4 89

A (71%) Procedure 1, RT = 3.01 min. Purity 97%. Electrospray positiveion mode: m/z 351 (M + H)+. 4 4 90

A (74%) Procedure 1, RT = 2.93 min. Purity 94%. Electrospray positiveion mode: m/z 349 (M + H)+. 3 4 91

A (70%) Procedure 1, RT = 3.07 min. Purity 96%. Electrospray positiveion mode: m/z 365 (M + H)+. 4 4 92

A (73%) Procedure 1, RT = 2.90 min. Purity 96%. Electrospray positiveion mode: m/z 349 (M + H)+. 4 4 93

A (70%) Procedure 1, RT = 3.01 min. Purity 95%. Electrospray positiveion mode: m/z 365 (M + H)+. 4 94

A (46%) Procedure 1, RT = 2.70 min. Purity 100%. Electrospray positiveion mode: m/z 267 (M + H)+. 3 3 95

A (53%) Procedure 1, RT = 2.85 min. Purity 99%. Electrospray positiveion mode: m/z 301 (M + H)+. 4 4 96

A (54%) Procedure 1, RT = 2.91 min. Purity 99%. Electrospray positiveion mode: m/z 345, 347 (M + H)+. 4 4 97

A (52%) Procedure 1, RT = 2.62 min. Purity 92%. Electrospray positiveion mode: m/z 312 (M + H)+. 2 2 40

A (88%) Proedure 1, RT = 3.30 min. Purity 94%. Electrospray positive ionmode: m/z 403 (M + H)+. 2 98

C (66%) ¹H NMR (400 MHz, DMSO-d₆): δ: 0.9 (3H, m, CH3), 1.6 (1H, m CH2),2.2 (d, 2H, CH2), 2.5-2.6, (1H, m, CH2), 2.7 (6H, s, N(CH3)2), 3.4 (3H,s, CH3), 6.8 (1H, m, Furan), 7.1- 7.4 (3H, m, phenyl), 8.0 (1H, m,Furan), 12.3 (1H, 2s, NH). Procedure 2. RT = 2.73 min. Purity 100%.Electrospray positive ion mode: m/z 310 (M + H)+ 4 3 99

C (57%) ¹H NMR (400 MHz, DMSO-d₆): δ: 0.9 (3H, m, CH3), 1.6 (1H, m CH2),2.2 (d, 2H, CH2), 2.5-2.6, (1H, m, CH2), 3.4 (3H, s, CH3), 6.8 (1H, m,Furan), 7.3 (1H,, m, Furan), 7.7 (2H, m, Phenyl), 8.1 (1H, m, Phenyl),12.2 (1H, 2s, NH). Procedure 4. RT = 8.03 min; Purity 98%. Electrospraypositive ion mode: m/z 335 (M + H)+ 4 4 100

C (65%) 1H NMR (400 MHz, DMSO-d₆): δ 0.9 (3H, t, CH3), 1.7 (2H, quin,CH2), 2.2 (2H, d, CH2), 2.6 (3H, s, CH3), 3.4 (3H, s, CH3), 6.8 (2H, 2s,Furan), 7.3-7.4 (3H, m, aromate), 8.0 (1H, m, aromatic), 12.1 (1H, bd,NH) Procedure 2. RT = 2.78 min. Purity 99%. Electrospray positive ionmode: m/z 281 (M + H)+ 3 2 138

C (22%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (3H, s, CH₃), 7.00-7.80 (12H,m, aromatic H Indole, Furan, Phenyl)), 8.30 (1H, s, NH); 11.4 (1H, s,NH); 12.5 (1H, bs, NH) Procedure 2. RT = 2.76 min. Purity 98%.Electrospray positive ion mode: m/z 340 (M + H)+ 2 2 101

C (61%) ¹H NMR (400 MHz, DMSO-d₆): δ: 0.8 (3H, m, CH3), 1.5 (2H, m CH2),2.1 (s, 3H, CH3), 2.4 (2H, m, CH2), 6.7 (2H, s, Furan), 7.5-7.9 (4H, m,phenyl), 12.3 (1H, bs, NH). 3 4 102

C (15%) ¹H NMR (400 MHz, DMSO-d₆): δ: 0.9 (3H, m, CH3), 1.6 (2H, m CH2),2.2 (d, 2H, CH2), 2.6 (3H, m, CH3), 4.0 (3H, s, OCH3) 6.8 (2H, s,Furan), 7.0- 7.4 (3H, m, phenyl), 8.1 (1H, m, aromate) 12.2 (1H, bs,NH). Procedure 2. RT = 2.73 min. Purity 100%. Electrospray positive ionmode: m/z 297 (M + H)+ 3 103

C (41%) 1H NMR (400 MHz, DMSO-d6): δ: 0.9 (3H, t, CH3), 1.6 (2H, m,CH2), 2.1-2.2 (2H, m, CH2), 2.3 (6H, s, 2 CH3), 2.5 (3H, s, CH3), 6.5(1H, s, furan), 6.8 (1H, s, furan), 7.2-7.3 (3H, m, aromatic), 12.0 (1H,bd, NH); Procedure 2. RT = 2.79 min. Purity 96%. Electro- spray positiveion mode: m/z 295 (M + H)+ 3 3 104

C (57%) ¹H NMR (400 MHz, DMSO-d₆): δ: 0.9 (3H, m, CH3), 1.6 (1H, m CH2),2.2 (d, 2H, CH2), 2.5-2.6, (1H, m, CH2), 3.4 (3H, s, CH3), 6.9 (1H, m,Furan), 7.3 (1H,, m, Furan), 7.9 (2H, d, Phenyl), 8.1 (2H, d, Phenyl),12.3 (1H, 2s, NH). Procedure 3. RT = 4.17 min. Purity 95%. Electrospraypositive ion mode: m/z 335 (M + H)+; negative ion mode 333 (M − H)− 3 3139

C (46%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (3H, s, CH₃), 6.8 (1H, s,Furan), 7.0 (1H, s, Furan), 7.2-7.8 (7H, m, aromatic), 8.3 (1H, s,aromatic), 12.5 (1H, bs, NH); Procedure 3. RT = 3.37 min. Purity 96%.Electrospray positive ion mode: m/z 385 (M + H)+ 3 4 4 31a

C (6%) Procedure 2. RT = 3.32 min. Purity 98%. Electrospray positive ionmode: m/z 387 (M + H)+ 3 1 106

C (64%) Procedure 4. RT = 7.93 min; Purity 98%. Electrospray positiveion mode: m/z 307 (M + H)+ 4 4 107

C (40%) Procedure 2. RT = 2.12 min. Purity 95%. Electrospray positiveion mode: m/z 365 (M + H)+ 1 1 108

C (28%) ¹H NMR (400 MHz, DMSO-d₆): δ 0.9 (3H, m, CH3), 1.6 (2H, m CH2),2.2 (d, 2H, CH2), 2.5 (3H, s, CH3), 6.9-7.6 (7H, m, aromatic), 11.4 (1H,bs, NH), 12.1-12.5 (1H, bs, NH) Procedure 2. RT = 2.69 min. Purity 99%.Electrospray positive ion mode: m/z 306 (M + H)+ 2 2 109

C (33%) Procedure 6. RT = 11.74 min, Purity 93%. Electrospray positiveion mode: m/z 335 (M + H)+ 4 2 61

C (59%) 1H NMR (400 MHz, DMSO-d₆): δ 2.6 (3H, s, CH3), 3.4 (3H, s, CH3),6.8- 8.0 (11H, m, aromatics), 12.6 (1H, bs, NH); Procedure 2. RT = 2.92min. Purity 97%. Electrospray positive ion mode: m/z 315 (M + H)+ 3 1

C (37%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (3H, s, CH₃), 7.0-8.4 (10H, m;Phenyl), 12.8 (1H, bs, NH); Procedure 3. RT = 4.11 min. Purity 95%.Electrospray positive ion mode: m/z 369 (M + H)+ 4 4 4 62

C (11%) Procedure 2. RT = 2.96 min. Purity 95%. Electrospray positiveion mode: m/z 329 (M + H)+ 3 110

C (58%) 1H NMR (400 MHz, DMSO-d6): δ 0.6 (3H, m, CH3), 1.4 (2H, m, CH2),1.9 (2H, m, CH2), 2.3 (3H, s, CH3), 6.4 (1H, m, furan), 6.6 (1H, m,furan), 7.0-7.5 (2H, m, phenyl), 8.0 (1H, s, phenyl), 11.5- 12.0 (1H,vbs, NH); Procedure 2. RT = 2.73 min. Purity 99%. Electrospray positiveion mode: m/z 351 (M + H)+ 3 3 111

C (9%) Procedure 4. RT = 7.98 min; Purity 92%. APCI positive ion mode:m/z 353 (M + H)+ 3 71

C (40%) 1H NMR (400 MHz, DMSO-d6): δ: 2.4 (3H, s, CH3), 2.7 (6H, s,N(CH3)2), 7.0-8.1 (11H, m, aromatic), 12.7 (1H, s, NH); Procedure 3. RT= 4.22 min. Purity 95%. Electrospray positive ion mode: m/z 344 (M + H)+3 140

C (53%) Procedure 2. RT = 3.12 min. Purity 100%. Electrospray positiveion mode: m/z 341 (M + H)+ 4 2 141

C (32%) Procedure 2. RT = 2.21 min. Purity 93%. Electrospray positiveion mode: m/z 399 (M + H)+ 1 1 142

C (59%) 1H NMR (400 MHz, DMSO-d6): δ: 3.4 (3H, s, CH3), 7.0-8.3 (11H, m,Furan, Phenyl), 12.7 (1H, bs, NH); Procedure 2. RT = 3.16 min. Purity100%. Electrospray positive ion mode: m/z 369 (M + H)+ 4 4 4 45

C (60%) ¹H NMR (400 MHz, DMSO-d₆): δ: 3.4 (3H, s, CH₃), 7.0-8.2 (11H, m,Furan, Phenyl), 12.7 (1H, s, NH); Procedure 2. RT = 3.17 min. Purity99%. Electrospray positive ion mode: m/z 369 (M + H)+ 4 3 3 143

C (72%) 1H NMR (400 MHz, DMSO-d6): δ 2.6 (3H, s, CH3), 6.8 (1H, m,furan), 7.0 (1H, m, furan), 7.2-7.8 (12H, m, alkene H, phenyl), 12.7(1H, bs, NH); Procedure 3. RT = 4.20 min. Purity 99%. Electrospraypositive ion mode: m/z 327 (M + H)+ 3 144

C (9%) ¹H NMR (400 MHz, DMSO-d₆): δ: 2.5 (3H, s, CH3), 6.5 (1H, s,Indole), 6.9 (2H, s, aromatic, Furan), 7.3 (1H, d, Furan), 7.4-7.8 (9H,m, aromatics), 11.2 (1H, s, NH), 12.7 (bs, 1H, NH). Procedure 2. RT =2.79 min. Purity 99%. Electrospray positive ion mode: m/z 340 (M + H)+ 33 3 34

C (41%) ¹H NMR (400 MHz, DMSO-d₆): δ: 3.4 (3H, s, CH₃), 7.0-7.9 (11H, m,Furan, Phenyl), 12.7 (1H, s, NH); Procedure 5. RT = 10.48 min; Purity98%. Electrospray positive ion mode: m/z 385 (M + H)+ 3 4 4 145

C (52%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.4 (3H, s, CH₃), 6.8, 7.0 (2H, d,Furan), 7.1-7.8 (9H, m, aromatic), 8.2 (1H, s, aromatic), 12.6 (1H, bs,NH); Procedure 2. RT = 2.64 min. Purity 92%. Electrospray positive ionmode: m/z 317 (M + H)+ 2 2 1 146

C (54%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (3H, s, CH₃), 7.0 (1H, s,Furan), 7.2- 7.8 (8H, m, aromatic), 8.2 (1H, s, aromatic), 12.5 (1H, bs,NH); Procedure 2. RT = 2.93 min. Purity 98%. Electrospray positive ionmode: m/z 319 (M + H)+ 3 3 3 147

C (44%) ¹H NMR (400 MHz, DMSO-d₆): δ 3.3 (3H, s, CH₃), 7.0-7.8 (9H, s,aromatic), 8.1-8.3 (1H, m, aromatic), 12.7 (1H, s, NH); Procedure 2. RT= 2.98 min. Purity 97%. Electrospray positive ion mode: m/z 337 (M + H)+4 4 4 148

C (53%) ¹H NMR (400 MHz, DMSO-d₆): δ: 2.4 (3H, s, CH3), 6.9, 7.1 (2H, d,Furan), 7.3-8.2 (9H, m, aromatics), 12.7 (bs, 1H, NH). Procedure 2. RT =2.88 min. Purity 98%. Electrospray positive ion mode: m/z 319 (M + H)+ 33 3 149

C (40%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (3H, s, CH₃), 6.9-7.8 (11H, m,aromatic), 8.2 (1H, s, aromatic), 10.2 (1H, bs, NH), 12.5 (1H, bs, NH);Procedure 3. RT = 3.14 min. Purity 99%. APCI positive ion mode: m/z 317(M + H)+ 1 2 1 150

C (16%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (3H, s, CH₃), 6.9-7.8 (11H, m,aromatic), 12.5 (1H, s, NH); Procedure 2. RT = 2.63 min. Purity 99%.Electrospray positive ion mode: m/z 317 (M + H)+ 2 2 2 35

C (44%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (3H, s, CH3), 7.1-8.6 (10H, m,aromatic), 12.8 (1H, bs, NH); Procedure 2. RT = 3.60 min. Purity 98%.Electrospray positive ion mode: m/z 437 (M + H)+ 2 3 1 31

C (52%) ¹H NMR (400 MHz, DMSO-d₆): δ 3.4 (3H, s, CH₃), 4.0 (s, 3H, OCH3)6.8- 7.0 (2H, m, Furan,) 7.1-8.0 (8H, m; Phenyl), 12.6-12.7 (1H, m, NH);Procedure 2. RT = 3.09 min. Purity 98%. Electrospray positive ion mode:m/z 399 (M + H)+ 4 3 3 151

C (39%) Procedure 2. RT = 2.54 min. Purity 96%. Electrospray positiveion mode: m/z 356 (M + H)+ 1 152

C (58%) ¹H NMR (400 Mhz, DMSO-d₆): δ 2.5 (3H, s, CH₃), 6.5 (1H, s,aromatic), 6.9-7.2 (2H, m, aromatic), 7.4- 7.8 (7H, m, aromatic), 7.9(1H, s, aromatic, )8.2 (1H, s, aromatic), 11.3 (1H, bs, NH), 12.5 (1H,bs, NH); Procedure 2. RT = 2.86 min. Purity 94%. APCI positive ion mode:m/z 340 (M + H)+ 3 3 3 153

C (77%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (3H, s, CH₃), 7.0, 7.2 (2H, d,Furan), 7.3-8.0 (7H, m, aromatic), 8.2 (1H, s, aromatic), 12.5 (1H, bs,NH); Procedure 3. RT = 3.67 min. Purity 98%. Electrospray positive ionmode: m/z 337 (M + H)+; negative ion mode m/z 335 (M − H)− 3 3 3 154

C (74%) Procedure 3. RT = 2.69 min. Purity 90%. Electrospray positiveion mode: m/z 367 (M + H)+; negative ion mode 365 (M − H)− 2 2 2 155

C (8%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (3H, s, CH₃), 6.6 (1H, s,aromatic), 7.0 (2H, s, aromatic) 7.3-7.8 (5H, m, aromatic), 8.2 (2H, d,aromatic), 11.3 (1H, s, OH), 12.5 (1H, bs, NH); Procedure 3. RT = 3.35min. Purity 96%. Electrospray positive ion mode: m/z 385 (M + H)+ 3 3 2156

C (26%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (3H, s, CH₃), 7.0-8.2 (11H, m,aromatic), 12.7 (1H, bs, NH), 13.2 (1H, s, NH); Procedure 3. RT = 3.00min. Purity 95%. Electrospray positive ion mode: m/z 341 (M + H)+ 1 157

C (48%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (3H, s, CH₃), 6.9-7.9 (9H, m,aromatic), 8.2 (1H, s, aromatic), 12.5 (1H, bs, NH); Procedure 5. RT =9.58 min; Purity 90%. APCI positive ion mode: m/z 351 (M + H)+ 3 3 2 32

C (46%) ¹H NMR (400 MHz, DMSO-d₆): δ 3.5 (3H, s, CH₃), 7.0-8.2 (10H, m;Phenyl), 12.8 (1H, bs, NH); Procedure 2. RT = 3.35 min. Purity 98%.Electrospray positive ion mode: m/z 403 (M + H)+ 3 4 3 158

C (8%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (3H, s, CH₃), 6.8-7.9 (9H, m,aromatic), 8.1 (1H, s, aromatic), 12.5 (1H, bs, NH); Procedure 2. RT =2.81 min. Purity 98%. Electrospray positive ion mode: m/z 351 (M + H)+;negative ion mode 349 (M − H)− 3 4 4 159

C (71%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (3H, s, CH₃), 6.9-8.2 (12H, m,aromatic), 12.6 (1H, bs, NH); Procedure 2. RT = 2.92 min. Purity 93%.Electrospray positive ion mode: m/z 341 (M + H)+ 3 3 1 160

C (53%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.6 (3H, s, CH₃), 6.9-8.3 (12H, m,aromatic), 11.7 (1H, s, NH), 12.6 (1H, bs, NH); Procedure 2. RT = 2.98min. Purity 98%. APCI positive ion mode: m/z 340 (M + H)+ 3 2 161

C (65%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.5 (3H, s, CH₃), 6.6, 7.1 (2H, d,Furan), 7.2-7.8 (10H, m, aromatic), 11.0 (1H, s, NH), 12.5 (1H, bs, NH);Procedure 2. RT = 2.94 min. Purity 100%. Electrospray positive ion mode:m/z 340 (M + H)+ 3 3 4 112

E (22%) 1H NMR (300 MHz, DMSO) δ 11.83 (d, 1H, NH), 8.14 (s, 1H),7.92-7.70 (m, 3H), 7.67-7.51 (m, 1H), 7.14 (s, 1H), 2.37 (br. s., 2H),2.19-1.92 (m, 3H, methyl), 1.66-1.43 (m, J = 7.1 Hz, 2H), 0.87 (t, J =7.1 Hz, 3H) Procedure 8. RT = 8.98 min. Purity 99.8%. Electrospraypositive ion mode: m/z 335 (M + H)+ 4 3 113

D (29%) 1H NMR (300 MHz, DMSO) δ 11.87 (d, 1H, NH), 7.92-7.79 (m, 2H),7.78- 7.69 (m, 1H), 7.69-7.54 (m, 2H), 7.51 (s, 1H), 2.37 (br. s., 2H),2.20- 1.97 (m, 3H, methyl), 1.64-1.40 (m, J = 7.3 Hz, 2H), 0.87 (t, J =7.3 Hz, 3H) Procedure 8. RT = 9.18 min. Purity 98.2%. Electrospraypositive ion mode: m/z 351 (M + H)+ 4 3 72

E (13%) 1H NMR (300 MHz, DMSO) δ 12.30 (s, 1H, NH), 8.36-8.16 (m, 1H),7.87 (m, 2H), 7.82-7.74 (m, 1H), 7.71- 7.61 (m, 2H), 7.61-7.51 (m, 1H),7.50-7.43 (m, 1H), 7.38 (m, 2H), 73.2-7.13 (m, 1H), 2.45-2.32 (d, 3H,methyl) Procedure 8. RT = 9.43 min. Purity 99.2%. Electrospray positiveion mode: m/z 369 (M + H)+ 2 114

D (36%) 1H NMR (300 MHz, DMSO) δ 11.22 (d, 1H), 7.83 (d, 1H), 7.76-7.67(m, 1H), 7.66-7.58 (m, 1H), 7.54 (d, 1H), 4.33 (d, J = 3.7 Hz, 2H), 4.22(d, J = 3.7 Hz, 2H), 2.53-2.33 (m, J = 7.1 Hz, 2H), 2.15-2.02 (d, 3H,methyl), 1.62-1.37 (m, 2H), 0.85 (t, J = 7.1 Hz, 3H) Procedure 9. RT =4.88 min. Purity 95.1%. Electrospray positive ion mode: m/z 409 (M + H)+3 115

D (24%) 1H NMR (600 MHz, DMSO) δ 12.09- 11.84 (m, 1H), 7.85 (d, 1H),7.78- 7.71 (m, 1H), 7.69-7.62 (m, 1H), 7.47 (d, 1H), 7.28-7.13 (m, 1H),2.49-2.46 (m, 1H), 2.33 (t, J = 7.1 Hz, 1H), 2.14-2.02 (d, 3H, methyl),1.92 (s, 3H, methyl), 1.61-1.43 (m, J = 7.4 Hz, J = 7.1 Hz, 2H),0.92-0.72 (m, J = 7.4 Hz, 3H) Procedure 8. RT = 9.16 min. Purity 99.8%.Electrospray positive ion mode: m/z 365 (M + H)+ 4 60

F (7%) 1H NMR (400 MHz, DMSO) δ 12.56 (s, 1H, NH), 7.88-7.66 (m, 2H),7.66- 7.21 (m, 4H), 7.21-7.05 (m, 2H), 7.02-6.95 (m, 1H, furan), 6.93(d, J = 3.1 Hz, 1H, furan), 2.44 (s, 3H, methyl), 2.41 (s, 3H,C6H4—CH3). Procedure 7. RT = 1.220 min, Purity 96.5%. Electrospraypositive ion mode: m/z 333 (M + H)+ 3 3 1 39

F (56%) 1H NMR (500 MHz, DMSO) δ 12.25 (br s, 1H, NH), 8.23 (s, 1H),8.16 (d, J = 7.5 Hz, 1H), 7.77-7.58 (m, 3H), 7.49-7.36 (m, 2H), 7.34-7.26 (m, 1H), 7.26-7.11 (m, 2H), 2.48 (s, 3H, methyl). Procedure 7. RT =1.340 min, Purity 90.8%. Electrospray positive ion mode: m/z 403 (M +H)+ 4 3 3 3

F (7%) 1H NMR (500 MHz, DMSO) δ 12.60 (br s, 1H, NH), 8.22 (d, J = 7.9Hz, 1H), 7.65 (d, J = 7.4 Hz, 2H), 7.53- 7.32 (m, 4H), 7.32-7.14 (m,3H), 6.99-6.96 (m, 1H, furan), 2.49 (s, 3H, methyl). Procedure 7. RT =1.218 min, Purity 100%. Electrospray positive ion mode: m/z 335 (M + H)+4 3 2 162

F (33%) Procedure 7. RT = 1.189 min, Purity 100%. Electrospray positiveion mode: m/z 319 (M + H)+ 3 3 3 52

F (43%) Procedure 7. RT = 1.094 min, Purity 100%. Electrospray positiveion mode: m/z 315 (M + H)+ 4 1 2

F (93%) 1H NMR (500 MHz, DMSO) δ 12.67 (s, 1H, NH), 8.25-8.02 (m, 1H),7.91-7.66 (m, 2H), 7.64 (d, J = 7.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 2H),7.47-7.33 (m, 2H), 7.33-7.16 (m, 1H), 7.16-6.80 (m, 1H), 2.44 (s, 3H,methyl). Procedure 7. RT = 1.251 min, Purity 95.6%. Electrospraypositive ion mode: m/z 369 (M + H)+ 3 1 163

F (52%) Procedure 7. RT = 1.120 min, Purity 95.8%. Electrospray positiveion mode: m/z 337 (M + H)+ 3 53

F (81%) Procedure 7. RT = 1.221 min, Purity 96.2%. Electrospray positiveion mode: m/z 329 (M + H)+ 3 3 1 164

F (66%) Procedure 7. RT = 1.105 min, Purity 96.2%. Electrospray positiveion mode: m/z 333 (M + H)+ 3 3 165

F (92%) Procedure 7. RT = 1.365 min, Purity 96.2%. Electrospray positiveion mode: m/z 357 (M + H)+ 2 166

F (95%) Procedure 7. RT = 1.079 min, Purity 96.9%. Electrospray positiveion mode: m/z 319 (M + H)+ 1 1 1 167

F (96%) Procedure 7. RT = 1.054 min, Purity 95.3%. Electrospray positiveion mode: m/z 301 (M + H)+ 1 1 74

F (62%) Procedure 7. RT = 1.127 min, Purity 97.1%. Electrospray positiveion mode: m/z 317 (M + H)+ 3 13

F (29%) Procedure 7. RT = 1.286 min, Purity 100%. Electrospray positiveion mode: m/z 395 (M + H)+ 2 57

F (68%) 1H NMR (500 MHz, DMSO) δ 12.50 (s, 1H, NH), 8.56 (s, 1H,oxazole), 7.96 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 7.4 Hz, 2H), 7.43-7.35(m, 4H), 7.22 (t, J = 7.1 Hz, 1H), 2.47 (s, 3H, methyl), 2.39 (s, 3H,methyl) Procedure 7. RT = 1.161 min, Purity 94.3%. Electrospray positiveion mode: m/z 316 (M + H)+ 3 8

F (14%) 1H NMR (500 MHz, DMSO) δ 11.65 (s, 1H, NH), 7.68-7.60 (m, 2H),7.61 (d, J = 8.5 Hz, 2H), 7.48-7.40 (m, 1H), 7.37 (d, J = 8.5 Hz, 2H),7.20-7.15 (m, 2H), 6.40-6.30 (m, 1H), 2.46-2.26 (m, 6H, 2xCH3), 2.01 (s,3H, methyl). Procedure 7. RT = 1.086 min, Purity 96.3%. Electrospraypositive ion mode: m/z 362 (M + H)+ 3 1 11

F (96%) 1H NMR (400 MHz, DMSO) δ 12.49 (s, 1H, NH), 8.35-8.05 (m, 2H),8.01 (s, 1H, thiazole), 7.80-7.55 (m, 2H), 7.52-7.31 (m, 4H), 7.31- 7.12(m, 1H), 2.44 (s, 3H, methyl). Procedure 7. RT = 1.151 min, Purity92.5%. Electrospray positive ion mode: m/z 336 (M + H)+ 3 73

F (31%) Procedure 7. RT = 1.104 min, Purity 90.3%. Electrospray positiveion mode: m/z 302 (M + H)+ 2 14

F (52%) 1H NMR (500 MHz, DMSO) δ 12.49 (s, 1H, NH), 8.59-8.22 (m, 1H),8.22-7.90 (m, 2H), 7.90-7.59 (m, 3H), 7.59-6.66 (m, 4H), 2.44 (s, 3H,methyl). Procedure 7. RT = 1.246 min, Purity 98.7%. Electrospraypositive ion mode: m/z 396 (M + H)+ 3 116

F (25%) Procedure 7. RT = 1.071 min, Purity 97.5%. Electrospray positiveion mode: m/z 348 (M + H)+ 3 56

F (24%) 1H NMR (400 MHz, DMSO) δ 12.46 (s, 1H, NH), 8.10-7.91 (m, 3H),7.71 (d, J = 6.2 Hz, 2H, p-phenyl), 7.52-7.29 (m, 4H), 7.28-7.10 (m,1H), 2.44 (s, 3H, methyl2.38 (s, 3H, C6H4—CH3). Procedure 7. RT = 1.169min, Purity 100%. Electrospray positive ion mode: m/z 332 (M + H)+ 3 58

F (54%) Procedure 7. RT = 1.318 min, Purity 95.2%, Electrospray positiveion mode: m/z 370 (M + H)+ 4 36

F (32%) Procedure 7. RT = 1.248 min, Purity 100%. Electrospray positiveion mode: m/z 396 (M + H)+ 3 2 59

F (16%) Procedure 7. RT = 1.321 min, Purity 92.4%. Electrospray positiveion mode: m/z 368 (M + H)+ 3 117

F (11%) Procedure 7. RT = 1.192 min, Purity 98.0%. Electrospray positiveion mode: m/z 335 (M + H)+ 1 1 118

F (19%) Procedure 7. RT = 1.266 min, Purity 90.1%. Electrospray positiveion mode: m/z 395 (M + H)+ 1 54

F (25%) Procedure 7. RT = 1.194 min, Purity 96.5%. Electrospray positiveion mode: m/z 331 (M + H)+ 2 7

F (21%) 1H NMR (500 MHz, DMSO) δ 12.20 (br s, 1H, NH), 7.77-7.58 (m,4H), 7.58-7.49 (m, 1H), 7.38 (t, J = 7.0 Hz, 2H), 7.31 (d, J = 2.3 Hz,1H), 7.22 (t, J = 7.1 Hz, 1H), 7.15 (t, J = 7.9 Hz, 2H), 2.48 (s, 3H,methyl). Procedure 7. RT = 1.098 min, Purity 95.1%. Electrospraypositive ion mode: m/z 335 (M + H)+ 3 15

F (20%) 1H NMR (500 MHz, DMSO) δ 12.57 (s, 1H, NH), 7.84 (t, J = 7.1 Hz,1H), 7.69 (d, J = 7.4 Hz, 2H), 7.64-7.26 (m, 7H), 7.23 (t, J = 7.1 Hz,1H), 2.33 (s, 3H, methyl). Procedure 7. RT = 1.164 min, Purity 95.9%.Electrospray positive ion mode: m/z 335 (M + H)+ 3 46

F (45%) 1H NMR (500 MHz, DMSO) δ 12.89- 12.21 (m, 1H, NH), 7.91 (d, J =7.7 Hzl), 7.77 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.59 (d, J= 7.7 Hz, 1H), 7.53 (d, J = 3.7 Hz, 1H, thiophene), 7.49 (t, J = 7.7 Hz,1H), 7.40 (t, J = 7.6 Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H), 2.48 (s, 3H,methyl). Procedure 7. RT = 1.294 min, Purity 100%, Electrospray positiveion mode: m/z 385 (M + H)+ 3 2 6

F (47%) 1H NMR (500 MHz, DMSO) δ 12.54 (s, 1H), 7.71 (d, J = 8.4 Hz,2H), 7.69-7.58 (m, 2H), 7.55 (d, J = 3.7 Hz, 1H), 7.49-7.47 (m, 3H),7.45- 6.97 (m, 3H), 2.45 (s, 3H, methyl). Procedure 7. RT = 1.270 min,Purity 100%. Electrospray positive ion mode: m/z 351 (M + H)+ 3 9

F (46%) Procedure 7. RT = 1.194 min, Purity 90.3%. Electrospray positiveion mode: m/z 364 (M + H)+ 2 1 10

F (11%) Procedure 7. RT = 1.070 min, Purity 95.0%. Electrospray positiveion mode: m/z 382 (M + H)+ 2 55

F (41%) 1H NMR (500 MHz, DMSO) δ 13.04- 12.32 (m, 1H, NH), 8.20 (s, 1H,thiazole), 7.87 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 7.3 Hz, 1H), 7.59 (d,J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H),7.33 (d, J = 7.8 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 2.45 (s, 3H,methyl), 2.33 (s, 3H, methyl). Procedure 7. RT = 1.222 min, Purity 100%.Electrospray positive ion mode: m/z 332 (M + H)+ 3 12

F (58% 1H NMR (400 MHz, DMO) δ 12.79- 12.30 (m, 1H, NH), 7.85-7.52 (m,5H), 7.53-7.26 (m, 5H), 7.26- 7.07 (m, 1H, thiophene), 2.47 (s, 3H).Procedure 7. RT = 1.255 min, Purity 96.3%. Electrospray positive ionmode: m/z 351 (M + H)+ 3 119

F (77%) 1H NMR (500 MHz, DMSO) δ 11.68 (s, 1H, NH), 7.75-7.61 (m, 2H),7.61-7.52 (m, 1H), 7.52-7.43 (m, 2H), 7.43-7.27 (m, 3H), 7.22- 7.08 (m,1H), 6.40 (s, 1H, pyrrole), 2.41 (s, 3H, methyl), 2.33 (s, 3H, methyl),1.98 (s, 3H, methyl). Procedure 7. RT = 1.142 min, Purity 96.9%.Electrospray positive ion mode: m/z 346 (M + H)+ 1 1 69

G 1H NMR (500 MHz, CDCl3) δ 9.67 (br s, 1H, NH), 7.79 (d, J = 7.9 Hz,1H), 7.74 (d, J = 7.6 Hz, 1H), 7.69-7.50 (m, 1H), 7.58 (t, J = 7.5 Hz,1H), 7.45 (t, J = 7.6 Hz, 1H), 7.33-7.14 (m, 4H), 7.05 (d, J = 2.4 Hz,1H, furan), 6.80 (d, J = 2.9 Hz, 1H, furan), 2.49 (s, 3H, methyl).Procedure 7. RT = 1.309 min, Purity 100%. Electrospray positive ionmode: m/z 369 (M + H)+ 4 3 2 66

G 1H NMR (500 MHz, DMSO) δ 13.00 (s, 1H, NH), 8.21 (d, J = 7.1 Hz, 1H),8.04-7.72 (m, 1H), 7.72-7.40 (m, 4H), 7.39-7.11 (m, 3H), 7.07 (d, J =2.0 Hz, 1H, furan), 6.98 (d, J = 2.0 Hz, 1H, furan), 2.36 (s, 3H,methyl). Procedure 7. RT = 1.288 min, Purity 100%. Electrospray positiveion mode: m/z 385 (M + H)+ 4 3 2 33

F 1H NMR (500 MHz, DMSO) δ 11.97 (s, 1H, NH), 7.93 (d, J = 7.3 Hz, 1H),7.82 (t, J = 6.9 Hz, 1H), 7.77-7.50 (m, 4H), 7.50-7.29 (m, 3H), 7.29-7.07 (m, 1H), 6.99 (s, 1H), 6.74 (s, 1H), 2.40 (s, 3H, methyl).Procedure 7. RT = 1.060 min, Purity 100%. Electrospray positive ionmode: m/z 368 (M + H)+ 2 3 1 168

F & H 1H NMR (500 MHz, DMSO) δ 14.86 (s, 1H, OH), 10.51 (s, 1H, NH),8.02 (t, J = 9.0 Hz, 1H), 7.83-7.09 (m, 7H), 7.13-6.15 (m, 2H), 2.43 (s,3H, methyl). Procedure 7. RT = 0.992 min, Purity 98.5%. Electrospraypositive ion mode: m/z 335 (M + H)+ 3 3 3 120

F & H 1H NMR (500 MHz, DMSO) δ 10.22 (s, 1H, OH), 9.45 (s, 1H, OH), 7.86(t, J = 8.8 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H, p-pheynyl), 6.89 (d, J =3.3 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H, p- pheynyl), 6.78-6.47 (m, 4H),2.37 (s, 3H, methyl). Procedure 7. RT = 0.965 min, Purity 93.8%.Electrospray positive ion mode: m/z 351 (M + H)+ 3 2 2 19

F & H (20%) 1H NMR (500 MHz, DMSO) δ 8.32- 8.29 (m, 1H), 8.18 (d, J =7.6 Hz, 1H), 7.75-7.09 (m, 7H), 6.99 (d, J = 3.4 Hz, 1H, furan), 6.96(d, J = 3.4 Hz, 1H, furan), 2.18 (s, 3H, methyl). Procedure 7. RT =1.226 min, Purity 98.0%. Electrospray positive ion mode: m/z 419 (M +H)+ 4 1 1 20

F & H (16%) 1H NMR (500 MHz, DMSO) δ 12.66 (s, 1H, NH), 8.00 (d, J = 7.7Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.79 (t, J = 7.5 Hz, 1H), 7.61 (t, J= 7.5 Hz, 1H), 7.58-7.12 (m, 4H), 6.96 (d, J = 2.8 Hz, 1H, furan), 6.90(d, J = 2.9 Hz, 1H, furan), 2.17 (s, 3H, methyl). Procedure 7. RT =1.179 min, Purity 100%. Electrospray positive ion mode: m/z 403 (M + H)+4 1 21

F & H (23%) 1H NMR (500 MHz, DMSO) δ 12.77 (s, 1H, NH), 8.17 (d, J = 7.4Hz, 1H), 7.87-7.16 (m, 7H), 7.16-6.62 (m, 2H), 2.45 (s, 3H, methyl).Procedure 7. RT = 1.404 min, Purity 100%. Electrospray positive ionmode: m/z 419 (M + H)+ 4 3 3 22

F & H (21%) Procedure 7. RT = 1.352 min, Purity 100%. Electrospraypositive ion mode: m/z 403 (M + H)+ 3 2 64

I (15%) 1H NMR (400 MHz, DMSO) δ 13.25 (s, 1H, NH), 8.22 (d, J = 7.6 Hz,1H), 7.79 (d, J = 7.4 Hz, 2H), 7.68-7.44 (m, 5H), 7.40 (t, J = 7.0 Hz,1H), 7.15 (d, J = 3.2 Hz, 1H, furan), 7.00 (d, J = 3.2 Hz, 1H, furan).Procedure 7. RT = 1.562 min, Purity 100%. Electrospray positive ionmode: m/z 405 (M + H)+ 4 2 65

I (9%) Procedure 7. RT = 1.480 min, Purity 100%. Electrospray positiveion mode: m/z 389 (M + H)+ 4 2 27

F (23%) 1H NMR (500 MHz, DMSO) δ 9.24 (br s, 1H, NH), 7.79 (d, J = 8.1Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.85-7.49 (m, 5H), 7.46 (t, J = 7.2Hz, 1H), 7.06 (d, J = 2.9 Hz, 1H, furan), 6.80 (d, J = 3.5 Hz, 1H,furan), 3.12 (s, 1H, acetylene), 2.51 (s, 3H, methyl). Procedure 7. RT =1.277 min, Purity 93.2%. Electrospray positive ion mode: m/z 393 (M +H)+ 4 41

F & H (40%) 1H NMR (500 MHz, CDCl3) δ 7.85 (br s, 1H, NH), 7.72-7.27 (m,8H), 6.98-6.92 (m, 1H, furan), 6.73- 6.69 (m, 1H, furan), 2.47 (s, 3H,methyl). Procedure 7. RT = 1.409 min, Purity 94.9%. Electrospraypositive ion mode: m/z 419 (M + H)+ 4 3 3 42

F (45%) 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H, NH), 7.67 (d, J = 8.3 Hz,1H), 7.61-7.49 (m, 2H), 7.45 (d, J = 7.5 Hz, 1H), 7.24 (d, J = 2.3 Hz,1H), 7.15-7.00 (m, 2H), 7.01-6.91 (m, 1H, furan), 6.82-6.71 (m, 1H,furan), 2.45 (s, 3H, methyl). Procedure 7. RT = 1.265 min, Purity 100%.Electrospray positive ion mode: m/z 421 (M + H)+ 4 4 4 43

F & H (35%) 1H NMR (500 MHz, CDCl3) δ 8.78 (br s, 1H, NH), 7.87-7.30 (m,5H), 7.21-7.01 (m, 2H), 7.01-6.85 (m, 1H, furan), 6.85-6.42 (m, 1H,furan), 2.45 (s, 3H, mehtyl). Procedure 7. RT = 1.43 min, Purity 93.9%.Electrospray positive ion mode: m/z 437 (M + H)+ 4 3 2 37

F & H (37%) 1H NMR (400 MHz, CDCl3) δ 7.67- 7.33 (m, 3H), 7.29 (t, J =7.7 Hz, 1H), 7.19-6.98 (m, 2H), 6.98- 6.81 (m, 1H), 6.81-6.46 (m, 1H),2.42 (s, 3H, methyl). Procedure 7. RT = 1.310 min, Purity 98.5%.Electrospray positive ion mode: m/z 403 (M + H)+ 4 3 3 44

F & H (42%) 1H NMR (500 MHz, DMSO) δ 8.13- 7.77 (m, 2H), 7.77-7.47 (m,3H), 7.60 (br s, 1H, NH), 7.39 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 3.3 Hz,1H), furan), 6.96-6.93 (m, 1H, furan), 2.47 (s, 3H, methyl). Procedure7. RT = 1.453 min, Purity 100%. Electrospray positive ion mode: m/z 453(M + H)+ 4 4 2 16

F & H (27%) 1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H, NH), 7.84-7.27 (m,4H), 7.20-6.42 (m, 5H), 2.43 (s, 3H, methyl). Procedure 7. RT = 1.249min, Purity 96.9%. Electrospray positive ion mode: m/z 387 (M + H)+ 3 44 47

F & H (16%) 1H NMR (500 MHz, CDCl3) δ 9.96 (br s, 1H, NH), 7.95-7.20 (m,8H), 7.16-6.91 (m, 1H, furan), 6.91- 6.67 (m, 1H, furan), 2.49 (s, 3H,methyl). Procedure 7. RT = 1.331 min, Purity 100%,. Electrospraypositive ion mode: m/z 403 (M + H)+ 4 4 3 48

F & H (61%) 1H NMR (400 MHz, DMSO) δ 12.67 (s, 1H, NH), 7.97 (d, J = 8.7Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.49-7.45 (m, 4H), 7.16 (d, J = 3.4Hz, 1H, furan), 6.96 (d, J = 3.4 Hz, 1H, furan), 2.46 (s, 3H, methyl).Procedure 7. RT = 1.322 min, Purity 100%. Electrospray positive ionmode: m/z 419 (M + H)+ 4 3 3 49

F (15%) H 1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H, NH), 8.19 (s, 1H,CH—C6H3), 7.98 (d, J = 7.9 Hz, 1H, p-C6H4), 7.92 (d, J = 8.2 Hz, 1H,p-C6H4), 7.82-7.49 (m, 2H), 7.44 (d, J = 3.4 Hz, 1H), 7.37-7.06 (m, 2H),7.07- 6.91 (m, 1H, furan), 2.47 (s, 3H, methyl). Procedure 7. RT = 1.379min, Purity 100%. Electrospray positive ion mode: m/z 421 (M + H)+ 3 3 250

F (14%) H 1H NMR (500 MHz, DMSO) δ 12.69 (s, 1H, NH), 8.17 (d, J = 1.6Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.66 (d, J= 8.3 Hz, 1H), 7.58 (dd, J = 34.4, 8.3 Hz, 1H), 7.45 (d, J = 8.4 Hz,2H), 7.29 (d, J = 3.4 Hz, 1H, furan), 6.96 (d, J = 3.4 Hz, 1H, furan),2.49 (s, 3H, methyl). Procedure 7. RT = 1.439 min, Purity 100%.Electrospray positive ion mode: m/z 453 (M + H)+ 3 3 2 67

G (4%) 1H NMR (400 MHz, CDCl3) δ 8.04- 7.85 (m, 1H), 7.85-7.71 (m, 1H),7.66 (s, 1H, imidazole), 7.42 (d, J = 7.9 Hz, 1H), 7.38-7.21 (m, 5H),7.19 (t, J = 7.2 Hz, 1H), 7.04 (d, J = 3.3 Hz, 1H, furan), 6.92 (d, J =3.4 Hz, 1H, furan). Procedure 7. RT = 1.628 min, Purity 100%.Electrospray positive ion mode: m/z 405 (M + H)+ 3 68

G (6%) 1H NMR (400 MHz, DMSO) δ 13.15 (s, 1H, NH), 8.21 (d, J = 8.2 Hz,2H), 7.96 (s, 1H, CH—C6H3), 7.64 (s, 1H, imidazole), 7.60-7.21 (m, 4H),7.12 (d, J = 3.3 Hz, 1H, furan), 6.99 (d, J = 3.3 Hz, 1H, furan).Procedure 7. RT = 1.628 min, Purity 100%. Electrospray positive ionmode: m/z 439 (M + H)+ 2 2 2 51

F (12%); H 1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H, NH), 8.23 (d, J = 8.6Hz, 1H), 7.81-7.59 (m, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.70-7.39 (m, 1H),7.34 (d, J = 2.1 Hz, 1H, furan), 7.31- 7.09 (m, 2H), 7.06-6.93 (m, 1H,furan), 2.46 (s, 3H, methyl). Procedure 7. RT = 1.293 min, Purity 95%.Electrospray positive ion mode: m/z 437 (M + H)+ 3 2 1 121

inactive inactive 122

inactive inactive

TABLE BB Antibacterial and cytotoxic activities of compounds of theinvention Antibacterial activity cyto- Bacterial species MRSA strainswith toxicity compound EC additional resistance cell line numberstructure SP ARSP MSSA MRSA SE BS EFm VREFm EFs VREFs MS Δ D V L M T P HK 1

4 4 4 4 3 3 1 2 4 4 4 3 4 3 2 2 2

3 3 1 1 1 3 1 1 2 1 3

4 3 2 2 3 1 4

4 4 2 3 2 5

4 4 3 3 2 6

3 3 2 2 0 0 7

3 1 2 8

3 1 2 1 9

3 1 3 2 10

3 3 2 11

3 1 2 12

3 1 2 13

3 1 1 14

3 1 1 15

3 3 2 1 1 1 16

3 4 4 4 3 3 1 1 1 3 1 17

3 3 4 1 4 1 1 3 3 18

3 4 4 3 3 4 1 1 1 1 1 4 4 4 4 4 4 2 2 19

4 3 1 1 1 2 3 1 3 3 0 20

4 3 1 1 3 0 21

4 4 4 3 1 3 1 1 1 4 3 3 3 2 22

3 2 2 23

4 4 4 3 1 4 1 1 1 1 3 2 24

4 4 3 3 1 3 1 1 4 4 3 3 4 2 2 2 25

3 1 0 0 26

3 2 1 0 27

4 1 2 28

3 1 1 4 1 0 29

3 3 2 30

4 4 3 3 2 3 1 4 2 1 3 3 31

4 3 3 3 0 31a

3 3 1 1 2 1 32

3 4 3 3 1 2 33

2 3 1 2 3 34

3 4 4 4 1 3 1 1 2 4 4 4 3 3 2 2 2 35

2 2 3 1 1 3 1 1 36

3 2 3 2 37

4 3 3 3 1 3 1 1 1 2 3 2 38

3 4 4 4 3 1 1 1 2 39

4 3 4 3 4 3 1 1 1 4 4 4 4 4 3 1 2 40

2 2 1 41

4 4 3 3 2 3 1 1 1 1 2 2 42

4 4 4 4 3 4 1 1 2 2 1 4 4 4 4 4 4 1 3 43

4 4 3 2 1 3 1 3 44

4 4 2 2 4 1 2 1 2 1 2 45

4 3 3 2 3 3 1 4 4 4 3 3 3 1 1 46

3 3 2 1 1 1 47

4 4 4 3 3 3 1 1 1 1 3 1 2 48

4 4 3 3 2 3 1 1 1 2 1 49

3 4 3 3 2 1 1 2 1 4 3 2 3 4 3 3 2 50

3 3 2 1 1 1 51

3 3 2 1 1 3 4 3 2 3 3 52

2 3 2 53

3 3 1 3 1 54

2 1 1 55

3 1 56

3 1 3 57

3 1 3 58

4 1 3 2 59

3 2 2 60

3 3 3 1 1 3 1 2 1 4 3 4 3 3 3 3 2 61

3 3 2 62

3 3 2 63

3 3 3 3 2 64

4 3 3 1 1 1 1 4 4 4 3 3 65

4 2 2 66

4 3 3 2 1 3 1 1 2 4 3 4 3 3 2 3 1 67

3 2 2 2 2 68

2 3 2 2 3 3 4 1 2 2 69

4 3 2 1 1 2 1 2 1 70

3 1 1 2 1 2 2 2 2 3 3 1 1 1 1 3 2 71

3 3 1 72

2 3 2 73

2 1 74

3 1 3 Streptococcus pneumoniae = SP multi-drug resistant-SP = ARSPStaphylococcus aureus MSSA = MSSA Staphylococcus aureus MRSA = MRSAStaphylococcus epidermidis = SE Bacillus substilis = BS Enterococcusfaecium = EFm vancomycin-resistant EFm = VREFm Enterococcus faecalis =EFs vancomycin-resistant EFs = VREFs Mycobacterium smegmatis = MSEscherichia coli ΔtoIC = EC Δ daptomycin = D vancomycin = V linezolid =L moenomycin = M triclosan = T platensimycin = P hepatocytes = Hkeratinocytes = K

The invention claimed is:
 1. An antimicrobial composition comprising acompound, said compound consisting of the structural moiety of formula(I) or a pharmaceutically-acceptable salt of said compound, for use as amedicament

wherein (i) Y is C; (ii) R¹ is selected from the group consisting of:—CH₃, C_(2to6)alkyl, an optionally substituted aryl ring, and anoptionally substituted benzyl ring, and (iii) R² is selected from thegroup consisting of: H, an alkyl group, a halogen, and —(CH₂)_(n)N(CH₃)₂where n is an integer from 1 to 3, with the proviso that at least one ofR¹ or R² possesses 3 or more carbon atoms; or R¹ and R² are connected toform a four-, five- or six-membered non-aromatic carbocyclic ring thusproviding a fused bicyclic moiety in which one or more of the carbonatoms of the ring comprising groups R¹ and R² is optionally replaced bya heteroatom selected from O, N, or S, and where one or more of theatoms of the ring comprising groups R¹ and R² is optionally substitutedwith one or more substituents independently selected from the groupconsisting of —CH₃, C_(2to4)alkyl, halogen, hydroxyl, —OCH₃,—OC_(2to4)alkyl, ethynyl, —OCF₃, and —CF₃; and (iv) A is selected fromthe group consisting of

where * is the point of connection to the correspondingly-labeled atomof B and ** is the point of connection to the correspondingly-labeledatom of

and wherein the aromatic ring of A is optionally substituted by one ormore substituents independently selected from —CH₃, C_(2to4)alkyl,halogen, OCH₃, and —OC_(2to4) alkyl; and (v) B is aryl.
 2. Theantimicrobial composition of claim 1, wherein B is an unsubstitutedphenyl ring or a substituted phenyl ring.
 3. The antimicrobialcomposition of claim 1, wherein B is a phenyl ring optionallysubstituted with one or more substituents independently selected fromthe group consisting of —CH₃, C_(2to4)alkyl, halogen, hydroxyl, —OCH₃,—OC_(2to4)alkyl, —CF₃, —OCF₃, —NH₂, —CH₂N H₂, —N(CH₃)₂, —NO₂, —CH₂OH,—CO₂CH₃, —CO₂C_(2to4)alkyl, —CO₂H, —N(alkyl)₂ where the two alkyl groupsare independently selected from —CH₃ or C_(2to4)alkyl, —NH(alkyl) wherethe alkyl group is selected from —CH₃ or C_(2to4)alkyl, 4-morpholinyl,1-piperidinyl, 4H-piperazinyl, 4-C_(1to4)alkyl-piperazinyl, and4-C_(3to6)cycloalkyl-piperazinyl.
 4. The antimicrobial composition ofclaim 1, wherein R¹ is substituted or unsubstituted phenyl.
 5. Theantimicrobial composition of claim 1, wherein R¹ is phenyl substitutedwith one or more substituents independently selected from the groupconsisting of —CH₃, C_(2to4)alkyl, halogen, hydroxyl, —OCH₃,—OC_(2to4)alkyl, ethynyl, —OCF₃, and —CF₃.
 6. The antimicrobialcomposition of claim 1, wherein the antimicrobial composition furthercomprises a pharmaceutically acceptable carrier.
 7. A combination of theantimicrobial composition of claim 1 and at least one inhibitor ofbacterial lipid biosynthesis, wherein the combination treats a microbialinfection and/or a disorder, affliction or illness caused by or at leastin part by the microbial infection, where said microbial infection is abacterial infection.
 8. A combination as defined in claim 7, wherein thecombination is provided by combining the antimicrobial composition ofclaim 1 and the at least one inhibitor in a single formulation beforedosing or by dosing the antimicrobial composition of claim 1 and the atleast one inhibitor separately.
 9. The antimicrobial composition ofclaim 1, wherein the compound is selected from

or a combination thereof.
 10. The antimicrobial composition of claim 9,wherein the compound is selected from compounds 2, 6, 19, 25, 26, 48,and
 50. 11. The antimicrobial composition of claim 10, furthercomprising at least one inhibitor of bacterial lipid biosynthesis.